2. Ian Holloway - MHRA

8/12/2019 2. Ian Holloway - MHRA

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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

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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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Slide 22


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Slide 23


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Slide 24


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Slide 25


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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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Documents

2. Ian Holloway - MHRA