Advance Diploma in Env. Engg.

Course: EZ
Paper 23156, Pollution control and waste Management
Expected question: Explain the water quality requirement of Pharmaceuticals
industry.( Mark 5 )
(Compiled by Bharat Dighe)

Module 1: Specific water quality requirements: Pharmaceutical

 Major utilities in pharma industry

 An excipient or used for reconstitution of products,
 During synthesis,
 During production of the finished product or as a cleaning agent for rinsing
vessels, equipment, primary packaging Material
 Control of the quality of water, in particular the microbiological quality, is a
major concern
 Different grades of water quality are required depending on the different
pharmaceutical uses
 Unique chemical properties due to its polarity and hydrogen bonds
 Able to dissolve, absorb, adsorb or suspend many different compounds
 Control of the quality of water throughout the production, storage and
distribution processes, including microbiological and chemical quality, is a
major concern
 Certain microbiological tests may require periods of incubation
 Control of the microbiological quality of WPU is a high priority
 Some types of microorganism may proliferate in water treatment components
and in the storage and distribution systems
General principles: PWS
 Water production, storage and distribution systems should be designed,
installed, commissioned, qualified and maintained to ensure the reliable
production of water of an appropriate quality.
 Necessary to validate the water production process to ensure the water
generated, stored and distributed is not beyond the designed capacity and
meets its specification.
 The capacity of the system should be designed to meet the average and the
peak flow demand of the current operation
 Appropriate recirculation and turnover to assure the system is well controlled
chemically and microbiologically
 Initial validation (installation qualification (IQ), operational qualification (OQ)
and performance qualification (PQ
 Water sources and treated water should be monitored regularly for chemical,
microbiological and, as appropriate, endotoxin contamination.
 Performance of water purification, storage and distribution systems should
also be monitored
 Records of the monitoring results, trend analysis and any actions taken
should be maintained.
 Where chemical sanitization of the water systems is part of the bio
contamination control programme a validated procedure should be followed to
ensure that the sanitizing process has been effective and that the sanitizing
agent has been effectively removed.
European Pharmacopoeia
 The European Pharmacopoeia provides quality standards for the following
grades of water
 Water for Injections
 Purified Water
 Water for preparation of extracts
Potable Water
 Not covered by a pharmacopoeial monograph
 Must comply with the regulations on water intended for human
consumption of a quality equivalent to that defined in Directive 98/83/EC
 Testing essential manufacturer to confirm the quality of the water.
 Manufacture of active substances and in the early stages of cleaning
pharmaceutical manufacturing equipment
 To use for drinking
 Washing and extraction of crude drug.
 Preparations of products for external use

Water for Injections (WFI)

 water for the preparation of medicines for parenteral administration
 Water is used as a vehicle (water for injections in bulk)
 For dissolving or diluting substances
 Preparations for parenteral administration (sterilised water for injections).
 should be prepared from drinking-water (usually with further treatment)
 Production methods include, for example, double-pass RO coupled with other
suitable techniques such as ultra filtration and deionization.
 Purified Water
 Purified Water is water for the preparation of medicines other than those that
are required to be both sterile and a pyrogenic
 Purified Water which satisfies the test for endotoxins described in Ph. Eur.
monograph 0008 may be used in the manufacture of dialysis solutions.
 Purified water is used in the preparation of all medication containing water
except ampoules, injections, some official external preparations such as
liniments
 Cleaning of Equipment
 All types of test and assay
 Preparation of Bulk chemicals
 Preparation of media in microbiology
 De ionzation- Distillation –Ion exchange-RO- Filtration

Water Present as excipient final formulation

 Water is the most commonly used excipient in medicinal products: the
minimum quality of water selected depends on the intended use of the
product,
 According to a risk based approach to be applied as part of an overall control
strategy.
 WFI is required for those products intended for parenteral administration and
this includes solutions for haemofiltration and haemodiafiltration, peritoneal
dialysis, irrigation solution and biologics.
 Sterile ophthalmic, nasal/ear and cutaneous preparations should be prepared
using materials (water) designed to
 Ensure sterility
 To avoid the introduction of contaminants
 Growth of micro-organisms.
AS type/purpose Manufacturing step Minimum acceptable
quality of water

No requirement for Synthesis of all WFI

sterility intermediates of AS Water for
prior to final isolation preparation of
and purification steps extracts
Extraction of herbals
AS is fermentation Fermentation media Potable Water
product or biological and cell culture media

AS manufacture of Fermentation media PW

vaccines. and cell culture media

AS is in solution, Any step excluding PW

not sterile, and final isolation and WFI
intended for purification.
parenteral use. Final isolation and
purification

parenteral product. Final isolation and PW

purification

non-sterile vaccines Final isolation and PW

for non-parenteral purification
use.
 Cleaning/Rinsing PRODUCT TYPE Minimum acceptable
quality of water

Initial rinse Intermediates and AS Potable Water

Final rinse AS Use same quality of

water as used in the AS
manufacture

Initial rinse Medicinal products – Potable Water

including CIP of non sterile
equipment,

Final rinse Medicinal products – Purified Water or use

including CIP of non sterile same quality of water as
equipment used in manufacture of
medicinal product, if
higher quality than
Purified Water

Initial rinse Sterile products PW

including CIP of
equipment,

Final rinse Sterile non-parenteral Purified Water or use

including CIP of products same quality of water as
equipment used in manufacture of
medicinal product, if
higher quality than
Purified Water

Production of purified water

 Ion exchange, RO, ultrafiltration and/or electro-deionization processes and
distillation.
 URS
 feed-water quality and its variation over seasons
 Quantity of water required by the user
 Required water-quality specification
 Sequence of purification stages required
 Energy consumption
 Extent of pretreatment required to protect the final purification
 Performance optimization, including yield and efficiency of unit treatment-
process steps
 appropriately located sampling points designed in such a way as
 to avoid potential contamination
 Appropriate instrumentation to measure parameters-pH, flow ,Tempt

PW-consideration
 maintenance of minimum flow through the water generation system is
recommended at all times;
 control of temperature in the system by heat exchanger or plant room cooling
to reduce the risk of microbial growth (guidance value < 25 °C);
 provision of ultraviolet disinfection
 Selection of water-treatment components that can periodically be thermally
sanitized;
 Application of chemical sanitization (including agents such as ozone,
hydrogen peroxide and/or per acetic acid)
 Thermal sanitization at > 65 °C.

Production of WFI
 More robust technique based on phase change
 high-temperature operation of the process equipment
 URS:
 feed-water quality
 required water quality specification
 quantity of water
 optimum generator size or generators with variable control to avoid over-
frequent start/stop cycling
 blow-down and dump functions
 cool-down venting to avoid contamination ingress
Water storage and distribution systems
  key part of the whole system
 fully integrated with the water purification components of the system.
 Water used directly or, more frequently, it will be fed into a storage vessel for
subsequent distribution to points of use
 configured to prevent microbial proliferation and recontamination of the water
 subjected to a combination of online and o(ine
 monitoring to ensure that the appropriate water speci"cation is maintained.
MOC of contact part

 Materials that come into contact with WPU, including pipework, valves and
fittings, seals, diaphragms and instruments, should be selected to satisfy the
following objectives.
 Compatibility: compatibility and suitability of the materials should encompass
the full range of its working temperature and potential chemicals that will
come into contact with the system at rest, in operation and during sanitization.
 Prevention of leaching. All materials that come into contact with WPU should be
non-leaching at the range of working and sanitization temperatures of the system.
Corrosion resistance. PW and WFI are highly corrosive
General
 System sanitization and bioburden control
 Storage vessel requirements: Capacity
 Contamination control considerations
 Nozzles: be configured to avoid dead zones-microbiological contamination
 Vent filterers:bacteria-retentive, hydrophobic and should ideally be configured
to allow in situ testing of integrity. Offine testing is also acceptable.
 Pressure-relief valves and bursting discs :sanitary design
 Temperature control and heat exchangers
 Circulation pumps
 Bio contamination control techniques
 System sanitization and bioburden control
 Storage vessel requirements: Capacity
 Contamination control considerations
 Nozzles: be configured to avoid dead zones-microbiological contamination
 Vent filterers:bacteria-retentive, hydrophobic and should ideally be configured
to allow in situ testing of integrity. Offine testing is also acceptable.
 Pressure-relief valves and bursting discs :sanitary design
 Temperature control and heat exchangers
 Circulation pumps
Bio contamination control techniques
 maintenance of continuous turbulent flow circulation within water distribution
systems reduces the propensity for the formation of biofilms
 design should ensure the shortest possible length of pipework
 deadlegs in the pipework should be minimized
 pressure gauges should be separated from the system by membranes
 hygienic pattern diaphragm valves
 pipework for steam-sanitized systems should be sloped and fully drainable
Growth of microorganisms:
 ultraviolet radiation sources in pipework;
 maintaining the system heated (greater than 65 °C);
 sanitizing the system periodically using hot water (guidance
 temperature > 70 °C);
 sanitizing the system periodically using superheated hot water or
 Clean steam;
 Routine chemical sanitization using ozone or other suitable
 Chemical agents.
 When chemical sanitization is used, it is essential to prove that the agent has
been removed prior to using the water.
 Ozone can be effectively removed by using ultraviolet radiation
Operational Considerations- Qualifications
 Start-up and commissioning of water systems
 Planned, well-define, successful and well-documented commissioning and
qualification: essential precursor to successful validation .
 Qualification:DQ, IQ, OQ, and PQ.
 A test period of two week: monitoring the system
 chemical and microbiological testing
 continuously monitor the incoming feed-water
 Develop appropriate operating ranges Develop and finalize operating,
cleaning, sanitizing and maintenance procedures.
 Develop and refine test-failure procedure
 Continuous monitoring system
Maintenance of Water system
 defined frequency for system elements;
 the calibration programme
 SOPs for specific tasks
 control of approved spares
 Issue of a clear maintenance plan and instructions;
 Review and approval of systems for use upon completion of work
 record and review of problems and faults during maintenance.

System reviews
 changes made since the last review
 system performance
 reliability
 quality trends, failure events
 investigation
 out-of-specifications results from monitoring
 changes to the installation
 updated installation documentation
 log books
 The status of the current SOP list.
 corrective actions and preventative actions (CAPA)
Inspection of water systems

 a current drawing of the water system showing all equipment

 approved piping drawings (e.g. orthographic and/or isometric)
 a sampling and monitoring plan with a drawing of all sample points
 training programme for sample collection and testing
 the setting of monitoring alert and action levels
 monitoring results and evaluation of trends
 inspection of the last annual system review
 review of any changes made to the system
 review of deviations recorded and their investigation
 general inspection of system for status and condition;
 review of maintenance, failure and repair logs, calibration
Reference:
1. WHO good manufacturing practices: water for
Pharmaceutical use
2. Guideline on the quality of water for pharmaceutical use
EMA/CHMP/CVMP/QWP/496873/2018 dt.1 February 2021