Test Methods and Method Requirements

Report
Alia Shahzad
Head of QA / QC
Bayer Pakistan, Lahore Plant.
Introduction of Presenter

Complete Name:
Mrs. Alia Shahzad

Qualification:
B. Pharm (PU)
M. Phil – Pharmacology (PU)

Position in Bayer:
Head of QA / QC

Technical Experience:
17 years

Areas of Interest:
- Validations & Qualifications
- Aseptic Processing
- GMP Inspections & Compliance
- Compendial Harmonization
Alia Shahzad, Head of QA / QC
Water for Injection
Page 2
WATER FOR INJECTION
STORAGE, SAMPLING, TESTING
REQUIRTEMENTS AND QUALIFICATION
Alia Shahzad, Head of QA / QC
Water for Injection
Page 3
Contents of the Presentation
PART 1
Water Systems
PART 2
Monitoring - Sampling and Testing Frequencies
PART 3
Physical, Chemical and Microbiological Testing Parameters
PART 4
Testing Methods and Requirements
Alert and Action Levels
Documentation and Trending of Data Monitored
PART 5
Qualification and Requalification of Process Systems
PART 6
Particular Considerations for Water Systems
Alia Shahzad, Head of QA / QC
Water for Injection
Page 4
Definitions
Water systems
Water systems (water used for product compounding or final rinsing of
surfaces which will contact the product), are typically operated in the
temperate ranges hot, ambient and cold:
► Hot systems are operated above 70 °C
► Cold systems are operated in the range between 2°C and 10°C
► Ambient systems are operated in the range of the environment in which
the system is located.
Purified water systems can be operated at any temperature.
WFI systems are preferably operated hot and with continuous recirculation
to control microbial growth. When WFI is stored and distributed at cold or
ambient temperatures, special precautions are taken to prevent the
ingress and proliferation of microbial contaminants, as e.g. appropriate
sanitization cycles which are defined as part of the system qualification
Alia Shahzad, Head of QA / QC
Water for Injection
Page 5
Water Systems (1)
The water system distribution Configuration should allow for the continuous flow of water in the
piping by means of recirculation.
points of use
feed water
The use of non-recirculating, dead-end, or one-way systems or systems segments should be
avoided whenever possible.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 6
Water Systems (2)
http://www.nayagara.net/
Pharmaceutical water - used for product compounding or final
rinsing of surfaces - exists in different (compendial) qualities such as:
Preparation of the different types of water must be performed according to current USP and/or
European Pharmacopoeia requirements and - if applicable - according to other
pharmacopoeias (e.g. Japanese) and local requirements.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 7
Contents of the Presentation
PART 1
Water Systems
PART 2
Monitoring - Sampling and Testing Frequencies
PART 3
Physical, Chemical and Microbiological Testing Parameters
PART 4
Testing Methods and Requirements
Alert and Action Levels
Documentation and Trending of Data Monitored
PART 5
Qualification and Requalification of Process Systems
PART 6
Particular Considerations for Water Systems
Alia Shahzad, Head of QA / QC
Water for Injection
Page 8
Monitoring – General Requirements
 Water systems undergo periodic monitoring of the specified required characteristics.
 The monitoring program is based on the
results of the qualification* work and/or
according to the results of a risk assessment.
 Monitoring is performed according to written
procedures, describing in sufficient detail the
responsibilities for sampling, the sampling sites,
and the sampling frequencies.
 Typical minimum sampling frequencies for process systems are described in slide 11-12.
 Higher or lower sampling frequencies for specific processes or products are justified according to the
results of a risk assessment.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 9
Sampling
 Sampling sites must be selected based on a risk
evaluation and / or as result of the initial
qualification.
 Samples have to be taken from representative
locations within the distribution and processing
system.
 Selection of sampling sites must not compromise the quality (e.g.: microbiological status) of the system
being monitored.
 The sampling plan has to be dynamic allowing for adjustments to sampling frequency and locations
based on system performance trends.
 When routine monitoring points are reduced or increased, the reason for the change has to be
documented.
 Sampling practice must simulate the use of a process system during manufacturing,
for example where water for manufacturing is delivered through a hose,
sampling has to be performed through this hose.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 10
Monitoring – Typical Minimum Sampling & Testing Frequencies 1
Alia Shahzad, Head of QA / QC
Water for Injection
Page 11
Monitoring – Typical Minimum Sampling & Testing Frequencies 2
Alia Shahzad, Head of QA / QC
Water for Injection
Page 12
Monitoring – Typical Minimum Sampling & Testing Frequencies 3
Sampling Point & Point of Use
Sampling Point & Point of Use may or may not be the same (see the diagram below):
sampling point
sampling point
Preparation
Vessel
point of use
Alia Shahzad, Head of QA / QC
point of use
= sampling point
Water for Injection
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Monitoring – Typical Minimum Sampling & Testing Frequencies 4
Points of Use
Feed Water
Particle Filter
Ventilation Filter
Return
Mixed ion
exchange bed
UV
Disinfection
unit
Inflow
UV
disinfection
unit
Storage Tank
Pump
Particle Filter
Alia Shahzad, Head of QA / QC
Water for Injection
Page 14
Monitoring – Typical Minimum Sampling & Testing Frequencies 5
System-specific sampling points ► depend on the construction and the technical
conditions of the installation or system
(e.g. begin and end [=return] of the distribution
system).
Relevant sampling points
(API/Potable water)
► evenly distributed throughout the plant
(e.g. one sampling point per floor).
Critical points of use
► depend on the individual manufacturing
process
(e.g. from which water is taken…
- for cleaning product contacting surfaces
- during final crystallization of APIs
- for final rinsing of product contacting
- for aqueous granulation processes)
Selected sampling points
► not directly relevant for the production
(e.g. in cleaning/washing areas)
Selected sampling points for
Endotoxin testing
► where purified water is ultra-filtered to meet the
endotoxin specification)
Alia Shahzad, Head of QA / QC
Water for Injection
Page 15
Monitoring – Typical Minimum Sampling & Testing Frequencies 6
Inflow
Return
Alia Shahzad, Head of QA / QC
Water for Injection
Page 16
Monitoring – Typical Minimum Sampling & Testing Frequencies 7
System-specific sampling points ► depend on the constrction and the technical
conditions of the installation or system
(e.g. begin and end [=return] of the distribution
system).
Relevant sampling points
(API/Potable water)
► evenly distributed throughout the plant
(e.g. one sampling point per floor).
Critical points of use
► depend on the individual manufacturing
process
(e.g. from which water is taken…
- for cleaning product contacting surfaces
- during final crystallization of APIs
- for final rinsing of product contacting
- for aqueous granulation processes)
Selected sampling points
► not directly relevant for the production
(e.g. in cleaning/washing areas)
Selected sampling points for
Endotoxine testing
► where purified water is ultra-filtered to meet
the endotoxin specification)
Alia Shahzad, Head of QA / QC
Water for Injection
Page 17
Monitoring – Typical Minimum Sampling & Testing Frequencies 8
critical:
aqueous coating
Alia Shahzad, Head of QA / QC
Water for Injection
process-relevant
but not critical:
organic coating
Page 18
Monitoring – Typical Minimum Sampling & Testing Frequencies 9
System-specific sampling points ► depend on the constrction and the technical
conditions of the installation or system
(e.g. begin and end [=return] of the distribution
system).
Relevant sampling points
(API/Potable water)
► evenly distributed throughout the plant
(e.g. one sampling point per floor).
Critical points of use
► depend on the individual manufacturing
process
(e.g. from which water is taken…
- for cleaning product contacting surfaces
- during final crystallization of APIs
- for final rinsing of product contacting
- for aqueous granulation processes)
Selected sampling points
► not directly relevant for the production
(e.g. in cleaning/washing areas)
Selected sampling points for
Endotoxine testing
► where purified water is ultra-filtered to meet
the endotoxin specification)
Alia Shahzad, Head of QA / QC
Water for Injection
Page 19
Monitoring – Typical Minimum Sampling & Testing Frequencies 10
selected:
washing/cleaning
Alia Shahzad, Head of QA / QC
Water for Injection
Page 20
Contents of the Presentation
PART 1
Water Systems
PART 2
Monitoring - Sampling and Testing Frequencies
PART 3
Physical, Chemical and Microbiological Testing Parameters
PART 4
Testing Methods and Requirements
Alert and Action Levels
Documentation and Trending of Data Monitored
PART 5
Qualification and Requalification of Process Systems
PART 6
Particular Considerations for Water Systems
Alia Shahzad, Head of QA / QC
Water for Injection
Page 21
Physical, Chemical and Microbiological Testing Parameters
TEST MODULE
SPECIFICATIONS
REFERENCE
Appearance
Clear, Colorless Liquid
Ph. Eur. and USP
Conductivity
< 1.1 µS / cm (20oC) or values as per Ph. Eur. Table
Ph. Eur. and USP
Ammonium
Not more intense in color than reference,
corresponding to < 0.05 ppm
JP
Complies to the test
JP
Not more intense in color than reference,
corresponding to < 0.2 ppm
Ph. Eur. and JP
< 0.5 mg / L
Ph. Eur. and USP
Oxidizable Substances
Complies to the test
JP
Acidity or Alkalinity
Complies to the test
JP
Not more intense in color than reference,
corresponding to < 0.1 ppm
Ph. Eur. and JP
Complies to the test
JP
Residue on Evaporation
< 10 ppm
JP
Microbial Contamination
max. 10 cfu / 100 ml
Ph. Eur. and USP
< 0.25 EU / ml
Ph. Eur. and JP
Chlorides
Nitrates and Nitrites
Total Organic Carbon (TOC)
Heavy Metals
Sulfates
Bacterial Endotoxins
Alia Shahzad, Head of QA / QC
Water for Injection
Page 22
Contents of the Presentation
PART 1
Water Systems
PART 2
Monitoring - Sampling and Testing Frequencies
PART 3
Physical, Chemical and Microbiological Testing Parameters
PART 4
Testing Methods and Requirements
Alert and Action Levels
Documentation and Trending of Data Monitored
PART 5
Qualification and Requalification of Process Systems
PART 6
Particular Considerations for Water Systems
Alia Shahzad, Head of QA / QC
Water for Injection
Page 23
Test Methods and Method Requirements
 All methods must be performed according to
current USP and/or European Pharmacopoeia
and, if applicable other pharmacopoeia and/or
local requirements (e.g. in case of potable water).
 All methods or culture media have to be suitable
to detect microorganisms that may be present.
The cultivation conditions, are selected to be
appropriate for the specific growth requirements
of microorganisms to be detected, for example:

Total aerobic count can be obtained by incubating at 30 to 35 °C for not less than three
days

Suitable culture media (low nutrient medium) is used for monitoring of water systems (30
to 35°C, at least 5 days).
 Testing of viable monitoring samples is performed under aerobic conditions unless there are indications
that the process is at risk for contamination with anaerobic microorganisms.
 It must be assured that cleaning or disinfection agents remaining on surfaces sampled does not
interfere with microbial recovery when methods using culture media are applied.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 24
Contents of the Presentation
PART 1
Water Systems
PART 2
Monitoring - Sampling and Testing Frequencies
PART 3
Physical, Chemical and Microbiological Testing Parameters
PART 4
Testing Methods and Requirements
Alert and Action Levels
Documentation and Trending of Data Monitored
PART 5
Qualification and Requalification of Process Systems
PART 6
Particular Considerations for Water Systems
Alia Shahzad, Head of QA / QC
Water for Injection
Page 25
Alert and Action Level in Microbiological Monitoring (1)
 An Alert level in microbiological monitoring is that level of microorganisms that shows
significant differences from normal operating conditions.
 Alert levels are usually based upon historical information gained from the routine operation
of the process in a specific controlled environment.
Common procedure of setting alter level based on a set of at least 12 months data:
95% of all results < alert level AND 5 % of all results ≥ alert level
 In a new facility, these levels are based on prior experience from similar facilities/
processes.
Typically, the initial alert level is set to…
50 % of the action level (specification limit)
 Alert levels are re-examined and – if necessary – re-set at an established frequency.
Trends that show a deterioration of the environmental quality require respective CAPAs.
 An Action level is that specification level of microorganisms or particles that when
exceeded requires immediate follow-up and, if necessary, corrective action.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 26
Alert and Action Level in Microbiological Monitoring (2)
Procedures when an Alert level is exceeded
 Exceeding the Alert level does not necessarily require
a definitive corrective action, but it prompts at least
documented follow-up measures, as established in
a local procedure.
 These measures include but are not limited to the following:
o
Comparison with results obtained concurrently with other related sampling points.
o
Comparison with historical data from the same sampling point.
o
If possible re-sampling of the affected sampling point; routine sample(s) taken from the
affected point(s) within this period can be considered as resample.
no further Alert level => no
additional action
consecutive Alert level exceeding => escalation of
measures (e.g. following the procedures of exceeding
an Action level)
again Alert level exceeding => repetition of resampling according to the procedure described
above
Alia Shahzad, Head of QA / QC
Water for Injection
Page 27
Action and Alert Level in Microbiological Monitoring (3)
Procedures when an Action level is exceeded

As soon as an Action level excursion is reported,
“immediate corrective actions” and an investigation
have to be performed as described in a local procedure.

An evaluation of the potential impact this exceeding
has on manufactured products has to be made.

When a definitive cause for the excursion can be determined immediately, specific corrective actions
are performed before re-sampling starts.

Re-sampling of the affected points has to be performed immediately after the implementation of
“immediate / specific corrective actions”.

Monitoring critical sampling points includes routine identification of
microorganisms to the species (or, where appropriate, genus) level
at least when Alert and Action Levels are exceeded.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 28
Contents of the Presentation
PART 1
Water Systems
PART 2
Monitoring - Sampling and Testing Frequencies
PART 3
Physical, Chemical and Microbiological Testing Parameters
PART 4
Testing Methods and Requirements
Alert and Action Levels
Documentation and Trending of Data Monitored
PART 5
Qualification and Requalification of Process Systems
PART 6
Particular Considerations for Water Systems
Alia Shahzad, Head of QA / QC
Water for Injection
Page 29
Documentation and Trending of Monitoring Data

All monitoring activities are documented properly (typically on
form sheets which are laid down in SOPs).

The results from critical sampling locations must be
assignable to the respective activity at the time of sampling
(important in case of batch-related monitoring, i.e. the
environmental monitoring data must have a formal linkage to
product release as defined by procedures).

Monitoring data must be summarized on a periodic basis and
issued to the responsible senior management on a periodic
basis (e.g. via Product Quality Review).

Based on this summary, trends have to be evaluated and
corrective action to be defined, if appropriate.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 30
Q&A
Purified water systems have to be sampled (monitored) daily for microbiological
testing.
For chemical/physical testing of water systems, it is highly recommended to define the
last point of use (return) in the system as a routine sampling point.
Any Alert Level excursion initiates an immediate OoS-procedure.
Purified water with endotoxin limit is required for the final purification of a non-sterile
API to be used in a sterile parenteral Drug Product.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 31
Contents of the Presentation
PART 1
Water Systems
PART 2
Monitoring - Sampling and Testing Frequencies
PART 3
Physical, Chemical and Microbiological Testing Parameters
PART 4
Testing Methods and Requirements
Alert and Action Levels
Documentation and Trending of Data Monitored
PART 5
Qualification and Requalification of Process Systems
PART 6
Particular Considerations for Water Systems
Alia Shahzad, Head of QA / QC
Water for Injection
Page 32
Process Systems – General Qualification Provisions
Qualification is required for any process system (e.g. Water, Nitrogen, Clean Steam,
Compressed Air) …
•
that is involved in the manufacture of APIs (beginning with the
regulatory starting materials), Drug Products or intermediates
•
that may affect testing results of an API, Drug Product or
intermediate,
•
that is involved in final cleaning processes,
•
where the utility supplied directly contacts an API, Drug
Product or intermediate,
•
where the utility supplied comes in contact with surfaces
that have direct contact with APIs, Drug Products or intermediates,
… and, therefore, could have an impact on the quality of the API, Drug Product or
intermediate.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 33
Prerequisites for Qualification of Process Systems
Before beginning the qualification of a process system, the following documentation
has to be available:
Alia Shahzad, Head of QA / QC
Water for Injection
Page 34
Test Items for Qualification of Process Systems (1)
Following table outlines parameters and aspects to be checked, evaluated and tested within
the qualification study of a process system, provided that these are relevant for the particular
qualification (see following slide).
Alia Shahzad, Head of QA / QC
Water for Injection
Page 35
Test Items for Qualification of Process Systems (2)
Based on this table, the qualification team determines by means of a risk-based
approach …
 the sampling points, e.g. by answering the following questions…
 Which points of use are critical ?
 Which points of use are system-specific ?
 Is it necessary to realize a particular sampling point (due to the unattainability of the point of
use) ?
Usually, selected sampling
points include…
significant points of use
return loop
points prior to and after each
significant treatment step
storage tank
Alia Shahzad, Head of QA / QC
Water for Injection
Page 36
Requalification of Process Systems
For-Cause Requalification
Generally, in case of changes or modifications, the same test items apply for requalification as for initial
qualification. However, based on a risk evaluation, the extent of a requalification may be reduced in
comparison to the initial qualification.
Periodic Requalification
The following periodic requalification
intervals apply:
However, the regular evaluation of the
existing documentation such as…
 monitoring data,
 quarterly reports,
 change documentation,
 logbooks,
 maintenance/servicing documentation,
 technical reports
… equates to periodic requalification, provided that relevant
requalification item are appropriately covered.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 37
Contents of the Presentation
PART 1
Water Systems
PART 2
Monitoring - Sampling and Testing Frequencies
PART 3
Physical, Chemical and Microbiological Testing Parameters
PART 4
Testing Methods and Requirements
Alert and Action Levels
Documentation and Trending of Data Monitored
PART 5
Qualification and Requalification of Process Systems
PART 6
Particular Considerations for Water Systems
Alia Shahzad, Head of QA / QC
Water for Injection
Page 38
Particular Considerations for Water Systems (1)
In case of water systems, the qualification process entails a three-phase approach in order to
satisfy the objective of demonstrating the reliability and robustness of the system in service
over an extended period.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 39
Particular Considerations for Water Systems (2)
Phase 1:
 Initial phase, usually taking 2 to 4 weeks, serves to establish operating parameters and
procedures,
 Does not end until the system operates stable and within the required ranges,
 Might be shortened in case of modifications to a water system already in use.
Phase 2:
 Short-term control phase usually taking 2 to 4 weeks, serves to demonstrate consistent
operation within the established ranges,
 Before water is permitted to be used for pharmaceutical purposes, an interim qualification
report is required, documenting the successful completion of Phase 2.
 However, water can also be used for pharmaceutical purposes during this phase,
provided that the respective batches are not released until the interim qualification report
has been finalized.
Alia Shahzad, Head of QA / QC
Water for Injection
Page 40
Particular Considerations for Water Systems (3)
Phase 3:
 Long-term control phase usually taking 1 year, serves to demonstrate continuous and
consistent operation irrespectively of external and seasonal variations.
 Physico-chemical properties, microbial counts (as well as endotoxin where required) are
monitored and evaluated at close intervals,
 Where the season affects the quality of the feed water (e.g. potable water), sampling
should be increased.
 Phase 3 ends with the preparation of the final Qualification Report.
End of Presentation
Alia Shahzad, Head of QA / QC
Water for Injection
Page 41
Alia Shahzad, Head of QA / QC
Water for Injection
Page 42

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