Safeguarding public health

MHRA Inspections cold-chain

di i d bl d medicines and blood
Ian Holloway
Temperature Monitoring Educational Meeting
Birmingham

Birmingham
24 J une 2010
Sections
S1 Setting the scene the continuing problems S1 Setting the scene the continuing problems
with international and national transport and
local storage of cold chain items
S2 Quality systems, deviations and investigations
what are the Regulators concerns?
S3 Common deficiencies blood bank inspections
S4 Practical points and questions Improving S4 Practical points and questions. Improving
technologies
Slide 2

Increasing systemdemands
S1
Increasing system demands
Longer supply chains and consolidation of global g y g
manufacturing
More cold-chain products and requirements for
i l hi i t t special shipping temperatures
More clinical trials and transport of Investigational
Medicinal Products Medicinal Products
Increasing expectations from Regulators for
validation documentation and audit validation, documentation and audit
Global warming as a reality
Delays caused by global security requirements y y g y q
Slide 3

The problemwe face The problem we face

The complexity of global supply-chains across
continents and time-zones is such that we have
limited knowledge of the actual journey
conditions and a fault-free journey is a high j y g
target to achieve...
Slide 4

Distribution sector drivers

ExpensiveProduct
MidCost Product
LowCost Product
Expensive Product
Shipping Studies
Validated
Specialist Logistics
Mid Cost Product
Some validation
Mixed Logistics
Low Cost Product
No validation
Non-PharmaLogistics
Specialist Logistics
Non Pharma Logistics
Leftwards (Improvement) Drivers
Making the chain resistant to counterfeits
Regulators seeking assurance of GMP
standards
Availability of better services/equipment
Rightwards (Worsening) Drivers
Big pharma outsourcing to contractors in India and China
Virtual companies having less product and technical
knowledge
Cost controls
Slide 5

Cost controls
Major recall of products shipped to UK and The
Netherlands by uncontrolled sea freight Netherlands by uncontrolled sea-freight
111 Product Lines
Nearly 60C Nearly 60C
RH over 90% RH over 90%
30 to 50 days
This picture is for illustration
purposesonlyandtheshipand purposes only and the ship and
its operators are not in any way
associated with the incident
cited here.
Slide 6

Unacceptable sea transit of generics from India to the UK

Unacceptable shipment data was not examined by the QP prior to batch
approval
One datalogger in a 40 foot container and location was unknown and not
justified
Dataloggers not used in all shipments not always available Dataloggers not used in all shipments not always available
Datalogger sampling time not specified varied from 30 mins to 4 hours
Extreme temperature and humidity seen. Water leak in container?
Temperature and humidity cycled on 24 hour basis
One company produced a stability study 3 days at 50C which was not
representative of conditions experienced
Some API and bulk tablets shipped was packaging adequate?
Goods went from Mumbai to Colombo. Sat on docks for 2 days. Co only
became aware when detected by the inspector
Slide 7

became aware when detected by the inspector

Some potential problem areas with air freight
1.Airport coldroom operates at 0/1C 7. Product is shipped by road to p p
-used mainly for flowers
2. Load is split between different
holds in the aircraft - running at
pp y
another airport
8. Cargo area is long distance from
plane/loading unloading area holds in the aircraft running at
different temperatures
3. Load is left on the ramp in high or
lowtemperatures
plane/loading unloading area
9. Large temperature variations
within an aircraft hold
10 Poor communication between low temperatures
4. Load is bounced off the aircraft -
passengers take priority
5 H ld h ti i t t d b
10. Poor communication between
freight forwarder, ramp staff and
airline staff
11 N ibl t t 5. Hold heating is not turned on by
the pilot
6. Plane transfer is scheduled for a
11. No access possible to top-up
dry-ice
12. Customs open the container to
public holiday inspect the contents
Slide 8

Some potential problem areas with road freight

1. Poor loading resulting in bad air 7. Unit mapped and validated for full g g
circulation
2. Incorrect set-point on fridge unit
3 Load shifts and rests against side
pp
load then used with part loads
8. Doors left open for excessive
times - no curtains present 3. Load shifts and rests against side
of vehicle
4. Fridge unit switched off during
overnight stop to reduce noise
times no curtains present
9. Seals and insulation become
damaged
10 Sliding and roller doors overnight stop to reduce noise
5. Blocked circulation passages in
the floor
6 L d d t il t l
10. Sliding and roller doors
11. Vehicle designed for long single-
drop trips is used for local deliveries
12 D f t l d t t 6. Load and trailer are not cool
before loading
12. Defrost cycle does not operate
correctly
Slide 9

Some potential problem areas with coldrooms

1. Alarms set to wrong values after 7. Seals and insulation become g
maintenance
2. Items not unpacked before
storage
damaged
8. Condensate drain in poor location
or not adequately maintained storage
3. Excessively full resulting in poor
air circulation
4 Mould present on walls
or not adequately maintained.
9. Dirty fan unit and blades
10. Backup power supply missing or
does not switchover 4. Mould present on walls
5. Items stored on floor
6. Inadequate segregation between
t bl d j t d t k
does not switchover
11. Used to store products with
tighter storage limits than the room
d i acceptable and rejected stock design
12. Not remapped or validated after
changes to the storage layout.
Slide 10

Things are becoming harder!

Increasing systemdemands Increasing system demands
+
Deficiencies still being found Deficiencies still being found
+
Increased Regulatory concerns Increased Regulatory concerns
=
Increasing Regulatory Expectations..
Slide 11

A proposed way forward to provide more and better

i f ti information
A Regulatory Gap Regulatory Gap exists in some transportation systems
where facilities and systems are not validated inspected or where facilities and systems are not validated, inspected or
documented to normal GXP standards
M i th ti t t t t d GXP Moving the entire transport system towards a GXP
environment (especially in cases where logistics companies
are not specialised Pharma operators) p p )
QP may be able to certify parts of the chain as GXP
equivalent but seek more information for the general or non equivalent but seek more information for the general or non-
GXP elements
M f l hi i Move from several shipping
documents towards a
Distribution Batch Record
Slide 12

Release System
Quality and deviations
S2
Adequate Resources
Financial pressure. How to quantify?
QualitySystem
q
+
Documented. PQR adds
metrics
Quality System
St ff d t it t
+
Staff and management commitment
Vague and unmeasurable
QUALITY ??
Slide 13

Ian Holloway 2009

Quality commitment
A Quality Systemwithout staff and management commitment A Quality System without staff and management commitment
and adequate resources is unlikely to result in the
manufacture and supply of quality pharmaceuticals
Too often inspectors see a quality system without a
commitment to quality or without adequate resources commitment to quality or without adequate resources
The Quality System can be run as a bureaucratic
blamingsystemwith no positive benefits seen by blaming system with no positive benefits seen by
managers or staff.
Slide 14

Temperature deviations: practical considerations

d t i i li and staying in compliance
Regulators are concerned that in fragmented, non-
specialised distribution chain there may be a lowor partial specialised distribution chain there may be a low or partial
deviation capture rate
Low deviation
Not considered in product release
capture
Compromised product supplied
No investigation or CAPA
The Harm Cycle can repeat
Slide 15

Investigations need good data and good quality

information
What are we missing?
Amount
Deviations and data
Amount
Calibration& timing Calibration & timing
Number of samples
Quality
Slide 16

Frequent problems the MHRA finds with investigations

Investigation completed very rapidly Investigation completed very rapidly
Investigations should be thorough with timelines
notified to the Regulator
Investigation concludes the most probable cause as the origin
Should ensure less obvious causes are considered Should ensure less obvious causes are considered
Investigation concludes staff error as the cause Investigation concludes staff error as the cause
Retraining may solve part of the problem but the
systems may also need to be improved
Outcome is not notified to sister-sites with similar operations
Similar errors can be prevented by notification
Slide 17

Similar errors can be prevented by notification

Six suggestions for improving the deviation capture rate
Ensure that all contractors and service providers have a
telephone contact n mber (ideall ith 24/7 operation) for telephone contact number (ideally with 24/7 operation) for
reporting real and suspected problem issues
H t d d i t d t f t t k Have a standard script and report form to capture key
information
Ed t l t th t i f ti t d t th Educate employees to ensure that information reported to the
wrong person or department is still captured and acted upon
f Ensure Regulatory Departments in non-EU countries are fully
informed about the EU QP system
Have frequent meetings between the QP and Regulatory
Departments
Slide 18

Have robust change-control systems in place

Key areas for an effective transport strategy
Robust Quality Systems integrated with ICH and EU
regulatory guidelines regulatory guidelines
Strategy transposed into corporate policy guidelines and gy p p p y g
SOPs
E t bli h b h k d KPI d it ith ff ti Establish benchmarks and KPIs and monitor with effective
auditing programme
Ensure management are aware of ongoing performance data
and audit results
Take prompt action to terminate or change provider if
f d t i ti i i ifi t
Slide 19

performance deterioration is significant

Common deficiencies blood banks
S3
Common deficiencies blood banks
Slide 20

This section credit -Stephen Grayson Blood bank inspections Common

Deficiencies Mar 2010 on www.transfusionguidelines.org.uk
Common deficiencies blood banks
Slide 21

Common deficiencies blood banks

Slide 22

Common deficiencies blood banks

Slide 23

Common deficiencies blood banks

Slide 24

Common deficiencies blood banks

Slide 25

Common deficiencies blood banks

Slide 26

P ti l i t d ti
S 4
Practical points and questions
Frequency of checking alarms
W kl d i t t t t tti ft Weekly and important to ensure correct settings after
maintenance visits
Relation between Action and Alert alarms and use of delay time Relation between Action and Alert alarms and use of delay time
Alert alarm to operate before Action alarms.
Delay periods to be reasonable and not allow product
damage damage.
Alarm logs to be provided with suitable annotation where
necessary
Repeated alarm triggers need investigation to avoid a culture of Repeated alarm triggers need investigation to avoid a culture of
ignoring alarms
No delays on core temperature monitoring
Slide 27

Practical points and q estions Practical points and questions

When to discard product after excursions
When there is no supporting stability data
When there is any doubt about quality/efficacy
Discuss the concerns with the maker or MHRA Discuss the concerns with the maker or MHRA
Can another user in the chain also expose the product to
adverse conditions
Selection of temperature ranges
Must be suitable for all products stored in the area p
Ensure units are run at mid-range whenever possible
Allow for accuracy of measuring system (+/- 0.5 degC)
Slide 28

P ti l i t d ti Practical points and questions

Temperature monitoring in transit
Transit should be regarded as storage
Transit is inherently variable
Identification of where/causation of transit excursions is Identification of where/causation of transit excursions is
beneficial
Knowledge of temperature control and monitoring systems Knowledge of temperature control and monitoring systems
Where are the control and recording probes
What does the alarm mean
What are the set-points
What security measure are in place
What is the effect of power failure/ backup battery a s e e ec o po e a u e/ bac up ba e y
Slide 29

P ti l i t d ti Practical points and questions

Calibration
C lib ti h ll b t bl t ti l Calibration shall be traceable to national
standards
Calibration documents to be reviewed
and approved by QA and approved by QA
Frequency normally yearly or after
major changes
Validation
Follow a written protocol, documented
report and acceptance report and acceptance
Periodic revalidation a normal GMP
requirement
Principles of Quality by Design should c p es o Qua y by es g s ou d
be considered
Slide 30

Practical points and questions

Paper and electronic storage records
Shall be kept for at least 15 years
Electronic data may need to be migrated to new system
Paper records kept in secure archive with fire Paper records kept in secure archive with fire
prevention systems
Silent hours coverage Silent hours coverage
Continuous 24/7 alarm monitoring
Staff cover and contingency arrangements
Alternative storage areas to move stock
Emergency maintenance cover available
Slide 31

Technology availability dataloggers

Dataloggers are readily readily available and not too
expensive
Many can generate a PDF file at the recipient site
with no additional software
They can be read at the recipient site and not be
subject to delayed reading at the originator site
Early identification of problems means to better and Early identification of problems means to better and
more thorough investigations
If a load is split between different aircraft holds or part If a load is split between different aircraft holds or part
is mishandled this becomes known
They facilitate continuous improvement by showing
the date, time and approximate location where
problems occurred
Th l d h idit
Slide 32

They can also record humidity

Technology availability - expensive originator product
Envirotainers are active heating/cooling units
which are battery-powered.
They can maintain set product temperatures
for several days.
Some require dry-ice
Typical set-point range +2 to +25C
Photo:Envirotainer
Operational temperatures for unit -30C to
+49C
Other competitor products now marketed eg
AcuTemp RKN. Has 3 active probes plus
ambient temperature record and record of
door openings door openings
Good for high-value and small volumes. Several airlines and blue-chip
ld h i id ff h i
Slide 33

cold-chain providers offer these services

Specialist road transport providers
Canadian company uses vehicles
fitted with two fridge units each has an
independent fuel tank.
Site has dedicated cleaning facility.
I id i t d d i d ft Inside is steamed and rinsed after
each trip
Three temp probes in each trailer plus Three temp probes in each trailer plus
manual checks every two hours
Cross docking facility provided for Cross docking facility provided for
transfer at 2-8 C.
Slide 34

Specialist shipper providers

UK company with pre-qualified
shippers which are claimed to maintain pp
+15 to +25C for up to 96 hours
Products use conventional coolpacks Products use conventional coolpacks
which can be conditioned at room
temperatures and recycled
Volumes range from 10 to over 300
litres
Slide 35

Other specialist service providers

World Courier are a global cold
chain logistics provider. They chain logistics provider. They
have GMP compliant storage
facilities in may countries
including India Other services including India. Other services
include expedited customs
clearance
Many airlines are now offering
Pharma-Solutions eg KLM/Air Pharma-Solutions eg KLM/Air
France, BA, Austrian Airlines etc
Companies listed on slides 32 to 36 are
representative and there are additional
companies that can also be regarded as
specialists for Pharma work
Slide 36

specialists for Pharma work

Involvement of the Qualified Person in the distribution
chain: must check the following: chain: must check the following:-
that storage and transport facilities used by the that storage and transport facilities used by the
manufacturer do not affect adversely the quality of the
product p
that the organisations involved in the distribution chain are
approved by the MA holder
th t t h i l t i l ith th that technical agreements are in place with these
organisations
that container systems have been qualified that container systems have been qualified
that the distribution chain has been validated
that effective communication can be maintained throughout
the chain in the event of recalls
Slide 37

Conclusion
Th i i i b R l t th t ld h i d t There is increasing concern by Regulators that cold chain products
products are being damaged during shipment or storage at unacceptable
temperatures and humidities
Validation/Qualification is a normal GMP requirement. Increasing
regulatory interest in moving the entire supply-chain nearer to a normal g y g ppy
GMP environment
With outsourcing and move to third-world production transport design With outsourcing and move to third world production, transport design
needs to be considered early in the process
Thermal shock may influence degradation kinetics and cause problems at Thermal shock may influence degradation kinetics and cause problems at
any stage in the products shelf-life
S i li d bl hi i d t f it i t d Specialised blue-chip services and systems for monitoring, storage and
distribution are increasingly available
Slide 38

ian.holloway@mhra.gsi.gov.uk