Alia Shahzad Head of QA / QC Bayer Pakistan, Lahore Plant

Alia ShahzadHead of QA / QCBayer Pakistan, Lahore Plant.

Alia Shahzad, Head of QA / QC Water for Injection Page 2

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

Introduction of Presenter


WATER FOR INJECTION

STORAGE, SAMPLING, TESTING

REQUIRTEMENTS AND QUALIFICATION


Contents of the Presentation

PART 1Water Systems

PART 2Monitoring - Sampling and Testing Frequencies

PART 3Physical, Chemical and Microbiological Testing Parameters

PART 4Testing Methods and RequirementsAlert and Action LevelsDocumentation and Trending of Data Monitored

PART 5Qualification and Requalification of Process Systems

PART 6Particular Considerations for Water Systems


Definitions

Water systems

► 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

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:


Water Systems (1)

The water system distribution Configuration should allow for the continuous flow of water in the

piping by means of recirculation.

The use of non-recirculating, dead-end, or one-way systems or systems segments should be

avoided whenever possible.

storag

e tan

k

feed water

points of use

loop


Water Systems (2)

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.

http://www.nayagara.net/



PART 1Water Systems







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.


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.


Monitoring – Typical Minimum Sampling & Testing Frequencies 1



Presentation Topic


Sampling Point & Point of Use

PreparationVessel

point of use point of use= sampling point

sampling pointsampling point

Sampling Point & Point of Use may or may not be the same (see the diagram below):



UVDisinfection

unit

Points of Use

Return

Storage Tank

Mixed ionexchange bed

Particle Filter

Pump

Ventilation Filter

Particle Filter

UVdisinfection

unit

Feed Water

Inflow



System-specific sampling points

Relevant sampling points(API/Potable water)

Critical points of use

Selected sampling points

Selected sampling points for Endotoxin testing

► depend on the construction and the technical conditions of the installation or system(e.g. begin and end [=return] of the distribution system).

► evenly distributed throughout the plant (e.g. one sampling point per floor).

► depend on the individual manufacturingprocess(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)

► not directly relevant for the production(e.g. in cleaning/washing areas)

► where purified water is ultra-filtered to meet the endotoxin specification)



ReturnInflow







Selected sampling points for Endotoxine testing

► depend on the constrction and the technical conditions of the installation or system(e.g. begin and end [=return] of the distribution system).

► evenly distributed throughout the plant(e.g. one sampling point per floor).







process-relevantbut not critical:organic coating

critical:aqueous coating







Selected sampling points for Endotoxine testing

► depend on the constrction and the technical conditions of the installation or system(e.g. begin and end [=return] of the distribution system).

► evenly distributed throughout the plant(e.g. one sampling point per floor).







selected:washing/cleaning




PART 1Water Systems







Physical, Chemical and Microbiological Testing Parameters

TEST MODULE SPECIFICATIONS REFERENCEAppearance 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

Chlorides Complies to the test JP

Nitrates and Nitrites Not more intense in color than reference, corresponding to < 0.2 ppm

Ph. Eur. and JP

Total Organic Carbon (TOC) < 0.5 mg / L Ph. Eur. and USP

Oxidizable Substances Complies to the test JP

Acidity or Alkalinity Complies to the test JP

Heavy Metals Not more intense in color than reference, corresponding to < 0.1 ppm

Ph. Eur. and JP

Sulfates Complies to the test JP

Residue on Evaporation < 10 ppm JP

Microbial Contamination max. 10 cfu / 100 ml Ph. Eur. and USP

Bacterial Endotoxins < 0.25 EU / ml Ph. Eur. and JP



PART 1Water Systems







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.



PART 1Water Systems







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.

In a new facility, these levels are based on prior experience from similar facilities/

processes.

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.

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

Typically, the initial alert level is set to…

50 % of the action level (specification limit)


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

again Alert level exceeding => repetition of re-sampling according to the procedure described above

consecutive Alert level exceeding => escalation of measures (e.g. following the procedures of exceeding an Action level)


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.



PART 1Water Systems







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.


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.



PART 1Water Systems







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 theregulatory starting materials), Drug Products or intermediates

• that may affect testing results of an API, Drug Product orintermediate,

• that is involved in final cleaning processes,

• where the utility supplied directly contacts an API, DrugProduct or intermediate,

• where the utility supplied comes in contact with surfacesthat 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.


Prerequisites for Qualification of Process Systems

Before beginning the qualification of a process system, the following documentation has to be available:


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).


Test Items for Qualification of Process Systems (2)

Based on this table, the qualification team determines by means of a risk-basedapproach …

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


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 requalificationintervals 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.

“streamlined”requalificationapproach



PART 1Water Systems







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.



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.



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


THANKS

Documents

Alia Shahzad Head of QA / QC Bayer Pakistan, Lahore Plant