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Safeguarding public health
MHRA Inspections cold-chainme c nes an oo
Ian Holloway
Temperature Monitoring Educational Meeting
24 June 2010
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Sections
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
.technologies
Slide 2
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S1
Longer supply chains and consolidation of globalmanufacturing
More cold-chain products and requirements forspec a s pp ng empera ures
More clinical trials and transport of Investigational
Increasing expectations from Regulators for,
Global warming as a reality
Dela s caused b lobal securit re uirements
Slide 3
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The complexity of global supply-chains across
continents and time-zones is such that we havelimited knowledge of the actual journey
conditions and a fault-free ourne is a hi h
target to achieve...
Slide 4
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Distribution sector drivers
Shipping Studies
Validated
Some validation
Mixed Logistics
No validation
-
Leftwards (Improvement) Drivers
Making the chain resistant to counterfeits
Regulators seeking assurance of GMPstandards
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
Slide 5
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Major recall of products shipped to UK and The
-
111 Product Lines
30 to 50 days
This picture is for illustration
its operators are not in any way
associated with the incident
cited here.
Slide 6
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Unacceptable sea transit of generics from India to the UK
Unacceptable shipment data was not examined by the QP prior to batchapproval
One datalogger in a 40 foot container and location was unknown and notjustified
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 notrepresentative 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
Slide 7
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Some potential problem areas with air freight
1.Air ort coldroom o erates at 0/1C 7. Product is shi ed b road to
-used mainly for flowers
2. Load is split between different-
another airport
8. Cargo area is long distance from
different temperatures
3. Load is left on the ramp in high or
9. Large temperature variations
within an aircraft hold
4. Load is bounced off the aircraft -passengers take priority
.
freight forwarder, ramp staff andairline staff
. o ea ng s no urne on y
the pilot
6. Plane transfer is scheduled for a
. o access poss e o op-up
dry-ice
12. Customs open the container topublic holiday inspect the contents
Slide 8
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Some potential problem areas with road freight
1. Poor loadin resultin in bad air 7. Unit ma ed and validated for full
circulation
2. Incorrect set-point on fridge unit
load then used with part loads
8. Doors left open for excessive-.
of vehicle
4. Fridge unit switched off during
9. Seals and insulation become
damaged
5. Blocked circulation passages inthe floor
.
11. Vehicle designed for long single-drop trips is used for local deliveries
. oa an ra er are no coo
before loading
. e ros cyc e oes no opera e
correctly
Slide 9
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Some potential problem areas with coldrooms
1. Alarms set to wron values after 7. Seals and insulation become
maintenance
2. Items not unpacked before
damaged
8. Condensate drain in poor location
3. Excessively full resulting in poor
air circulation
.
9. Dirty fan unit and blades
10. Backup power supply missing or
.
5. Items stored on floor6. Inadequate segregation between
11. Used to store products withtighter storage limits than the room
accep a e an re ec e s oc es gn
12. Not remapped or validated after
changes to the storage layout.
Slide 10
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Things are becoming harder!
+ +
=
Increasing Regulatory Expectations..
Slide 11
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A proposed way forward to provide more and better
n orma onA Regulatory GapRegulatory Gap exists in some transportation systems
,documented to normal GXP standards
ov ng e en re ranspor sys em owar s aenvironment (especially in cases where logistics companiesare not s ecialised Pharma o erators
QP may be able to certify parts of the chain as GXP-
GXP elements
ove rom severa s pp ng
documents towards a
Distribution Batch Record
Slide 12
Release System
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Quality and deviationsS2
Ade uate Resources
Financial pressure. How to quantify?
+ Documented. PQR addsmetrics
+
ta an management comm tmentVague and unmeasurable
QUALITY ??
Slide 13
Ian Holloway 2009
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Quality 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
The Quality System can be run as a bureaucratic
managers or staff.
Slide 14
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Temperature deviations: practical considerations
and staying in compliance
Regulators are concerned that in fragmented, non-
deviation capture rate
Low deviationNot considered in product release
capture Compromised product supplied
No investigation or CAPAThe Harm Cycle can repeat
Slide 15
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Investigations need good data and good quality
informationWhat are we missing?
Deviations and data
Number of samples
Quality
Slide 16
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Frequent problems the MHRA finds with investigations
Investigations should be thorough with timelines
notified to the Regulator
Investigation concludes the most probable cause as the origin
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
Slide 17
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Six suggestions for improving the deviation capture rate
Ensure that all contractors and service providers have ae ep one con ac num er ea y w opera on orreporting real and suspected problem issues
ave a s an ar scr p an repor orm o cap ure eyinformation
uca e emp oyees o ensure a n orma on repor e o ewrong person or department is still captured and acted upon
Ensure Regulatory Departments in non-EU countries are fullyinformed about the EU QP system
Have frequent meetings between the QP and RegulatoryDepartments
Slide 18
Have robust change-control systems in place
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Key areas for an effective transport strategy
Robust Quality Systems integrated with ICH and EU
Strate trans osed into cor orate olic uidelines andSOPs
s a s enc mar s an s an mon or w e ec veauditing programme
Ensure management are aware of ongoing performance data
and audit results
Take prompt action to terminate or change provider if
Slide 19
per ormance e er ora on s s gn can
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S3
Slide 20
This section credit -Stephen Grayson Blood bank inspections Common
Deficiencies Mar 2010 on www.transfusionguidelines.org.uk
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Common deficiencies blood banks
Slide 21
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Common deficiencies blood banks
Slide 22
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Common deficiencies blood banks
Slide 23
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Common deficiencies blood banks
Slide 24
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Common deficiencies blood banks
Slide 25
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Common deficiencies blood banks
Slide 26
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S 4
Practical points and questionsFrequency of checking alarms
ee y an mpor an o ensure correc se ngs a ermaintenance visits
Alert alarm to operate before Action alarms.Delay periods to be reasonable and not allow product
.
Alarm logs to be provided with suitable annotation wherenecessary
ignoring alarmsNo delays on core temperature monitoring
Slide 27
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rac ca po n s an ques onsWhen 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
Can another user in the chain also expose the product to
adverse conditions
Selection of temperature ranges
Must be suitable for all roducts stored in the area
Ensure units are run at mid-range whenever possible
Allow for accuracy of measuring system (+/- 0.5 degC)
Slide 28
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Practical points and questionsTemperature monitoring in transit
Transit should be regarded as storage
Transit is inherently variable
Identification of where/causation of transit excursions is
beneficial
now e ge o empera ure con ro an mon or ng sys ems
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 ower failure/ backu batter
Slide 29
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Practical points and questionsCalibration
a ra on s a e racea e o na onastandards
Calibration documents to be reviewed
Frequency normally yearly or aftermajor changes
ValidationFollow a written protocol, documented
Periodic revalidation a normal GMPrequirement
Princi les of Qualit b Desi n shouldbe considered
Slide 30
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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
Pa er records ke t in secure archive with fireprevention systems
en ours coverage
Continuous 24/7 alarm monitoring
Staff cover and contingency arrangements
Alternative storage areas to move stock
Emergency maintenance cover available
Slide 31
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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
more thorough investigations
is mishandled this becomes known
They facilitate continuous improvement by showingthe date, time and approximate location where
problems occurred
Slide 32
ey can a so recor um y
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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 +25CPhoto:Envirotainer
Operational temperatures for unit -30C to+49C
Other competitor products now marketed egAcuTemp RKN. Has 3 active probes plusambient temperature record and record of
Good for high-value and small volumes. Several airlines and blue-chip
Slide 33
cold-chain providers offer these services
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Specialist road transport providers
Canadian company uses vehiclesfitted with two fridge units each has anindependent fuel tank.
Site has dedicated cleaning facility.ns e s s eame an r nse a er
each trip
ree emp pro es n eac ra er p us
manual checks every two hours
transfer at 2-8 C.
Slide 34
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Specialist shipper providers
UK company with pre-qualified
shi ers which are claimed to maintain
+15 to +25C for up to 96 hours
which can be conditioned at room
temperatures and recycled
Volumes range from 10 to over 300litres
Slide 35
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Other specialist service providers
World Courier are a global cold
have GMP compliant storage
facilities in may countries.include expedited customsclearance
Many airlines are now offering 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
Slide 36
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Involvement of the Qualified Person in the distribution
-
manufacturer do not affect adversely the quality of the
product that the organisations involved in the distribution chain are
approved by the MA holder
a ec n ca agreemen s are n p ace w ese
organisations
that the distribution chain has been validated
that effective communication can be maintained throughoutthe chain in the event of recalls
Slide 37
C l i
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Conclusion
ere s ncreas ng concern y egu ators t at co c a n pro ucts
products are being damaged during shipment or storage at unacceptable
temperatures and humidities
Validation/Qualification is a normal GMP requirement. Increasing
re ulator interest in movin the entire su l -chain nearer to a normalGMP environment
- ,
needs to be considered early in the process
any stage in the products shelf-life
pec a se ue-c p serv ces an sys ems or mon or ng, s orage an
distribution are increasingly available
Slide 38
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