maintenance and management of stability chambers and management of stability chambers ......

IVT – StabilityTesting EU

San Diego

12th-14th December 2016

CONFIDENTIAL ©2015 PATHEON®

Maintenance and Management ofStability Chambers

Geoff Carr

Introduction

In any stability study, it is claimed that samples were held for a certainperiod of time at defined temperature and humidity eg

o Real time - 25C±2C/40%RH±5%

o Accelerated - 40C±2C/75%RH±5%

o Intermediate - 35C±2C/65%RH±5%

CONFIDENTIAL ©2015 PATHEON®December 11, 2016 | 2

o Intermediate - 35C±2C/65%RH±5%

o Etc

o Very important to

Ensure that we are confident that these defined conditions were actuallyachieved over the duration of the study Have procedures in place for dealing with excursions

Have documentation available that will satisfy any auditor that these conditions were maintainedand any excursions correctly addressed

Introduction

For many pharmaceutical development groups and commercialanalytical support groups, it is normal for very large numbers ofstability studies to be in progress within several chambers

oWe maintain over 20 chambers running more than 500 studies

o Therefore we must


o Therefore we must

Put thorough systems in place to manage studies

Have security on access to chambers

Reconciliation of samples in chambers

Ensure that we have evidence of all this available as these studies willbe subject to regulatory audits

Introduction

This presentation will discuss some aspects of

oMetrology control of stability chambers

oManagement of stability studies

As follows


As follows

Main Menu

Introduction

What are Stability Chambers?

Some Approaches to Maintenance of Stability Chambers

Approaches to Management of Stability Programs

Conclusions


Conclusions

What Are Stability Chambers?

Stability chambers are available in many different shapes and sizesbut they are all designed to maintain various constant environmentalconditions over periods of time that could extend to several years ieo They must maintain various nominal conditions within defined narrow

tolerances as follows 25C±2C/60%RH±5%RH – Real Time


25C±2C/60%RH±5%RH – Real Time

40C±2C/75%RH±5%RH - Accelerated

30C±2C/65%RH±5%RH – Intermediate

5C±3C/Ambient RH – Refrigerator

-20C±5C/Ambient RH – Freezer

Photostability (Option 1 or 2)/Perhaps controlled temp/Perhaps controlled RH

Etc etc


Could be

o Large walk in chambers

o Smaller reach in chambers

o Bench top chambers

Choice may depend on


Choice may depend on

o The number of stability programs that require the condition

o Duration of the study at that condition

o Nature of samples

Capsules/tablets in blister packs likely to need less space than liquids inbottles that require storage at various orientations

Or large volume parenterals that can require vast volumes of space


Whichever type of chamber we are using, it is our responsibilityto ensure that they are maintaining the requiredtemp/humidity/light condition over the duration of the study

o And we must have documented evidence that this happened


Examples of our Powers and Lunair Chambers

Some Approaches to Maintenance of StabilityChambers

Maintenance of chambers includes

o Initial and subsequent qualifications

oConstant logging of chamber performance

o Alarm systems


o Alarm systems

o Back up systems


Initial and subsequent qualifications

o IQ/OQ/PQ

o Installation qualification (IQ)

Verifies that equipment and all ancillary systems have been installed in


Verifies that equipment and all ancillary systems have been installed inaccordance with installation drawings and equipment specifications

Inspection to ensure all systems work

Electrical checks

Functional checks


Operational Qualification

o Verifies that equipment capable of operating to required tolerancesfor intended purpose eg

Deliver required temperatures and humidities to required ±2C/±5%RH


o Achieved by mapping empty chamber

Map temperatures and humidities at several preselected locations eg 12locations

Mapping locations should be selected to include potential “hot” and“cold” spots

o Alarm systems operating correctly


Performance Qualification

o Verifies that equipment delivers required performance under normaloperating conditions

Achieved by further temperature/humidity mapping

For a new chamber to be done on completion of OQ and under worst


For a new chamber to be done on completion of OQ and under worstcase conditions ie with chamber full

Typically achieved by filling chamber with dummy units

Also conducted at several preselected locations

oRemapping should be conducted periodically eg annually

Conducted “as is”


Constant logging of chamber performance

oConducted using built in chamber monitoring systems

oChambers should include temperature and humidity probes

Provide continuous performance records


Provide continuous performance records

Could be in form of built in chamber loggers


Could be electronic monitoring

oWe use Rees monitoring system

oCollects temp/humidity data every 15 min from each chamber andsends to PC


o Also can activate pagers to call in Metrology if we get a chamberexcursion that requires attention


Important to maintain log books for access to chambers

oNeed to know when door was opened for any reason

Date and time

o Allows reconciliation with Rees record


o Allows reconciliation with Rees record

Opening chamber should correlate with a temp/humidity spike in record

Usually returns to normal within just a few minutes


Alarm Systemso For anyone running stability programs, be aware that

temperature/humidity excursions will happen at some time

o Therefore, important for companies to have SOPs that define approachesto dealing with themWhat are your temp/humidity tolerances?


What are your temp/humidity tolerances? Should be ±2C/±5%RH for normal conditions

As per ICH Q1A(R2)

Some companies apply tighter tolerances to “be on safe side” Don’t recommend this

Need to ensure that this would be within specification tolerances of chambers


Reason for temp/humidity excursions is that the 2 parameters arevery dependant on each other

o Note we are dealing with Relative Humidities not Absolute values

o The amount of water vapour that can be held by air (Saturated VapourPressure) is very much dependant on temperature = Dew Point eg


Pressure) is very much dependant on temperature = Dew Point eg

At 20C 1kg of air can hold 20g of water vapour

At 40C 1 kg of air can hold 50g of water vapour

Any fluctuations in temp will lead to corresponding fluctuations in relativehumidity


Not necessary to apply action for every excursion eg when chamberdoors are openedo It is necessary to have an SOP that defines acceptable excursions and

actions required if these are exceeded egWe allow excursions provided that required conditions restored within 24

hours


hours

SOP then defines that Deviation Report (DR) to be raised if this does notapply

Under what circumstances it may become necessary to evacuate chamber

To ensure that actions are taken promptly, Rees system sets off pagers toalert Metrology personnel

Alternative is audio alarm system


Back Up Systems

oWhat happens if chamber breaks down and cannot be repairedwithin a reasonable time

Evacuate but then what


oDepends on storage condition and whether space available inanother chamber set to the same conditions eg

If it’s a 40C/75%RH could stop clock and keep at 25C/60%RH untilchamber fixed then restart clock

Must describe intended approach in SOP


Dealing with power outages

o Best to have stability chambers on back up generator

Considered to be critical equipment

If not beware of 40C/75%RH and even more so, 30C/75%RH


If not beware of 40C/75%RH and even more so, 30C/75%RHconditions. As per previous discussion on relative humidities, aconsequence of chamber cooling could be flooding!!!!

Management of Stability Studies

When working with large numbers of stability programs veryimportant to apply a good management system to

o Prepare protocols

o Ensure correct samples pulled at the right times


o Ensure correct samples pulled at the right times

o Keep records of which chambers, samples are stored in

Particularly when there are a number of chsmbers for eachtemp/humidity condition

To maintain reconciliations of all samples in all studies


Requires a good record system which could be

o Paper system

Complex and time consuming when working with large numbers ofstability studies


o Software system


For securityo Keep chambers lockedRestricted access for stability co-ordinators For putting samples into chambers and removing them

Important to keep strict control on sample numbers for reconciliations of samples

Define in protocols the numbers of samples for each condition


o Define in protocols the numbers of samples for each conditionTake into account amounts required for testing

Include some spares

Log should then record Exact numbers of samples placed in each chamber

Numbers of samples removed at each pull point for each condition

Any additional samples removed with dates and reasons


Novatek is an example that provides:

o Location of samples in chambers

o Pull schedules

For each stability protocol


For each stability protocol

oDaily schedule

o Sample logs and reconciliations

o Part of the daily schedule for a couple of days earlier this monthlooks like:

Management of Stability StudiesDue Date Product Name Packaging Lot # # of Units Container Orientation Chamber Storage Condition Actual Time Point

Pull Date

Mar 8, 2010 Abcd Acetate Tablets 4800001923/HGX 0 Marlex Bottle Upright sample Chamber 11 30 +/- 2 °C and 65 +/- 5% RH Mar 08, 2010 2 Months

Abcd Acetate Tablets 4800001923/HGX 0 Marlex Bottle Upright sample Chamber 12 40 +/- 2 °C and 75 +/- 5% RH Mar 08, 2010 2 Months

Abcd Acetate Tablets 4800001923/HGX 0 Marlex Bottle Upright sample Chamber 13 30 +/- 2 °C and 75 +/- 5% RH Mar 08, 2010 2 Months

Altu-135 T325 Capsules C0968C001 0 HDPE bottle Upright sample Room 3 - Unit 19 25 +/- 2 °C and 60 +/- 5% RH Mar 08, 2010 36 Months

Altu-135 T325 Capsules C0956A001 0 HDPE bottle Upright sample Room 3 - Unit 19 25 +/- 2 °C and 60 +/- 5% RH Mar 08, 2010 36 Months

OPQ-906AA Tablets 4800001139/FNP 0 HDPE bottle Upright sample Chamber 19 40 +/- 2 °C and 75 +/- 5% RH Mar 08, 2010 1 Months

OPQ-906AA Tablets 4800001139/FNP 0 HDPE bottle Upright sample Chamber 16 5 +/- 3 °C and Amb.RH Mar 08, 2010 1 Months

OPQ-906AA Tablets 4800001191/FPD 0 HDPE bottle Upright sample Chamber 19 40 +/- 2 °C and 75 +/- 5% RH Mar 08, 2010 1 Months

OPQ-906AA Tablets 4800001191/FPD 0 HDPE bottle Upright sample Chamber 16 5 +/- 3 °C and Amb.RH Mar 08, 2010 1 Months

STUV Succinate Oral Suspension 4800000470/NHC 12 Amber PET Bottle Upright sample Room 2503 25 +/- 2 °C and 60 +/- 5% RH Mar 08, 2010 1 Months

STUV Succinate Oral Suspension 4800000470/NHC 12 Amber PET Bottle Inverted sample Room 2503 25 +/- 2 °C and 60 +/- 5% RH Mar 08, 2010 1 Months

STUV Succinate Oral Suspension 4800000470/NHC 10 Amber PET Bottle Upright (wt loss) sample Room 2503 25 +/- 2 °C and 60 +/- 5% RH Mar 08, 2010 1 Months

STUV Succinate Oral Suspension 4800002117/PTB 4 PET Bottle Upright sample Room 2503 25 +/- 2 °C and 60 +/- 5% RH Mar 08, 2010 1 Months

STUV Succinate Oral Suspension 4800002117/PTB 4 PET Bottle Upright sample Room 4023 40 +/- 2 °C and 75 +/- 5% RH Mar 08, 2010 1 Months

Mar 9, 2010 CDEF Tablets S0179C002_pkg. 3 0 HDPE bottle Upright sample Chamber 4 30 +/- 2 °C and 65 +/- 5% RH Mar 02, 2010 9 Months

CDEF Tablets S0179A001_pkg. 1 0 HDPE bottle Upright sample Chamber 4 30 +/- 2 °C and 65 +/- 5% RH Mar 02, 2010 9 Months

CDEF Tablets S0179A001_pkg. 1 0 HDPE bottle Upright sample Room 3 - Unit 12 25 +/- 2 °C and 60 +/- 5% RH Mar 02, 2010 9 Months



CDEF Tablets S0179B001_pkg. 2 0 HDPE bottle Upright sample Chamber 4 30 +/- 2 °C and 65 +/- 5% RH Mar 02, 2010 9 Months

CDEF Tablets S0179B001_pkg. 2 0 HDPE bottle Upright sample Room 3 - Unit 18 25 +/- 2 °C and 60 +/- 5% RH Mar 02, 2010 9 Months





CDEF Tablets S0179C001_pkg. 3 0 HDPE bottle Upright sample Room 3 - Unit 19 25 +/- 2 °C and 60 +/- 5% RH Mar 02, 2010 9 Months

CDEF Tablets S0179C001_pkg. 3 0 HDPE bottle Upright sample Chamber 4 30 +/- 2 °C and 65 +/- 5% RH Mar 02, 2010 9 Months


DEFG Sodium Topical Gel 4800001104/FNG 21 Round Bottle Inverted sample Chamber 9 40 +/- 2 °C and 75 +/- 5% RH Mar 09, 2010 1 Months

DEFG Sodium Topical Gel 4800001104/FNG 21 Round Bottle Upright sample Room 3 - Unit 28 25 +/- 2 °C and 60 +/- 5% RH Mar 09, 2010 1 Months

DEFG Sodium Topical Gel 4800001100/FNC 10 Round Bottle Inverted sample Chamber 9 40 +/- 2 °C and 75 +/- 5% RH Mar 09, 2010 1 Months

DEFG Sodium Topical Gel 4800001100/FNC 10 Round Bottle Upright sample Room 3 - Unit 27 25 +/- 2 °C and 60 +/- 5% RH Mar 09, 2010 1 Months

DEFG Sodium Topical Gel 4800001102/FNF 11 Round Bottle Inverted sample Chamber 9 40 +/- 2 °C and 75 +/- 5% RH Mar 09, 2010 1 Months













Conclusions

For any Group running GMP stability programs, management ofstudies very critical and includes

oManagement of chamber performance

oManagement of the studies held in the chambers

Maintenance of chambers requires


Maintenance of chambers requires

o IQ/OQ/PQ programs for each chamber

o Alarm systems and SOPs to deal with excursions

Particularly note close relationship of temp and RH in 40C/75%RH andeven more so, 30C/75%RH chambers

o Security to deal with power outages

Conclusions

Management of studies requires

o Protocol preparations

oRecords of which chambers samples are placed

o Logs for each chamber


o Logs for each chamber

oReconciliations of samples

o Pull schedules for each study

o Security

Chambers to be kept locked with access limited to Stability Co-ordinators

maintenance and management of stability chambers and management of stability chambers ......

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