Agua Purificada para uso farmacéutico según OMS

WHO TRS 970 (Informe 47), Anexo 2

Dr. Francisco J. Eguiguren

22 Abr 2020
Educational Background

•Pharmacist, Universidad Central del Ecuador, Quito-Ecuador, 1996

•“Introduction to GMPs for Pharmaceutical Products”, Universidad de Puerto Rico / FDA
•“Project Management”, Universidad Politécnica de Madrid, August 2006
•Advanced English, Wall Street Institute, Quito-Ecuador, November 2010
•Mastery in Process and Quality Management, Universidad Central del Ecuador - 2020

Associations membership and participation

 American Society for Quality (ASQ)

o Certified Pharmaceutical GMP Professional
o Regular member
 Ecuadorian Association of Innovative Laboratories
o Subject Matter Expert of GMP/GSP related topics in representation of Pfizer Ecuador
o Regular member
 Pichincha-Ecuador, Association of Chemist and Biochemist Professionals
o Speaker in GMP/GDP related conferences
o Regular member
Work Experience

 Pfizer – Quality Assurance Manager

 Grünenthal GmbH
 Quality Assruance Manager
 Regional QA Manager
 GMP Corporate auditor – 40 + GMP audits performed in China, India, Europe and Latam
 GMP Training & Cosulyting
 GMP senior consultant
OBJETIVOS del Webinar:
• Entender de manera sucinta, pero integral, el Anexo 2
del Informe 46 de la Organización Mundial de la Salud
“WHO good manufacturing practices: water for
pharmaceutical use”

• Conocer y diferenciar el uso de los distintos tipos de

Agua para Uso Farmacéutico.

• Conocer y diferenciar los sistemas de: Purificación,

Almacenamiento y Distribución de agua según OMS y
los principios de Calificación/Validación del sistema.
 Qué son los TRS de la
WHO?
http://www.who.int/medicines/publications/pharmprep/en/

Los TRS
El Comité de
“ El Comité de Expertos
Expertos en emite
Especificaciones anualmente
para los Technical
Preparaciones Report Series
Farmacéuticas se – TRS
reúne todos los
años y sus
Informes incluyen
Nomenclatura:
todas las Guías • “WHO Technical
adoptadas en Report Series 970”
forma de Anexos” • Informe 47, 2013
 Annex 2

“Good
Manufacturing Practices:
Water for Pharmaceutical
Use”
 ALCANCE y PROPOSITO DEL ANEXO 2, Informe 47

• which quality of water to use for specific applications ?

• Guidance on specifications (referred to

Pharmacopoeias)

• The guidelines may also be relevant to other industrial

or specific uses

• Nota: no cubre agua para administración a

pacientes o el uso de pequeñas cantidades de agua
en farmacias como componente individual en
prescripciones.
INTRODUCCION:

• Agua es la sustancia mas ampliamente utilizada

• Materia prima
• Estructura química única debido a su polaridad y
puentes de hidrógeno
• Capaz de disolver, absorber o suspender muchos
compuestos.

• Riesgos
• Contaminación o reacción con los componentes
de una fórmula
• Crucial eliminar toda posibilidad de
contaminación microbiana.
• Quality Control
• Alta prioridad
• Control Químico y Microbiológico.
• Durante producción, Almacenamiento y
distribución.
2. Principios Generales de los Sistemas de Agua Purificada

• Diseñados, instalados, calificados y mantenidos para

asegurar producción de agua de Calidad

• Capacidad adecuada

• Los sistemas de producción deben estar Validados (IQ, OQ,

PQ) … y tener mantenimiento regular

• Cambios, aprobados por quality assurance (QA) usando

Change Control

• Sanitización es parte de los programas de

biocontaminacion
.
3. Especificaciones

Drinking Water (DW)

Examples of natural sources include springs, wells, rivers, lakes

and the sea. The condition of the source water will dictate the
treatment required

Typical treatment includes desalinization, softening, removal

of specific
ions, particle reduction and antimicrobial treatment.

Derived from a public water supply that may be a combination

of more than one of the natural sources listed above.

It is also common for public water supply organizations to

conduct tests and guarantee that the drinking-water delivered
is of drinking quality.
3. Water quality specifications

Drinking-water

It is the responsibility of the pharmaceutical manufacturer to

assure that
the source water supplying the purified water (PW)

Drinking-water quality is covered by the WHO drinking-water

guidelines, standards from the International Organization for
Standardization (ISO)and other regional and national agencies.
3. Water quality specifications

Bulk purified water (BPW)

• Prepared from a drinking-water source as a minimum-

quality feed-water.

• It should meet the relevant pharmacopoeial specifications

for chemical and microbiological purity with appropriate
action and alert limits.

• It should also be protected from recontamination and

microbial proliferation.

• BPW may be prepared by:

• Reverse osmosis (RO)
• RO/electro-deionization (EDI)
• Vapour compression (VC).
3. Water quality specifications

Bulk highly purified wáter (BHPW)

Prepared from drinking water as a minimum-quality

feed-water.

BHPW is a unique specification for water found only in

the European Pharmacopoeia.

This grade of water must meet the same quality

standard as water for injections (WFI), including the
limit for endotoxins, but the water-treatment process
used may be different.

Current production methods include:

• Double-pass RO + ultrafiltration and deionization.

3. Water quality specifications

Bulk water for injections (BWFI)

• BWFI) should be prepared from drinking-water (usually with further

treatment) or purified water as a minimum-quality feedwater.

• BWFI is not sterile water and is not a final dosage form.

• It is an intermediate bulk product
• BWFI is the highest quality of pharmacopoeial WPU.

The International Pharmacopoeia and the European Pharmacopoeia

allow only distillation as the final purification step.

BWFI should meet pharmacopoeial specifications for chemical and

microbiological purity (including endotoxin)
4. Application of specific types of water to processes and dosage
forms

• The grade of water used should take into account the nature and
intended use.

• BHPW can be used in the preparation of products when water of

high quality (very low in microorganisms and endotoxins) is
needed.

• BWFI should be used in the manufacture of injectable and for

manufacture of sterile water for preparation of injections.

• BWFI should also be used for the final rinse after cleaning of
equipment and
components that come into contact with injectable products

Steam in contact with an injectable product in its final container

should conform to the specification for BWFI when condensed.
5. Water purification systems

General Considerations:
• water quality specification
• quantity of water required
• feed-water quality and the variation over time (seasonal changes)
• support facilities
• Raw water, electricity, heating steam, chilled water, compressed air, sewage system, exhaust air
• sanitization strategy;
• support and maintain the water purification equipment;
• continuity of operational usage considering hours/days, days/years and planned downtime;
• life-cycle costs (capital and operational including maintenance).
5. Water purification systems

General considerations

• location of the plant room

• temperature that the system will encounter
• the risk of contamination
• the adverse impact of adsorptive contact materials;
• hygienic or sanitary design, where required;
• corrosion resistance
• a system configuration to avoid proliferation of
microbiological organisms
• tolerance to cleaning and sanitizing agents (thermal
and/or chemical)
• ability to collect simples

should be monitored routinely

5. Water purification systems

Production of drinking wáter (DW)

DW is derived from a raw water source such as a well, river or reservoir.

There are no prescribed methods for the treatment of raw water to

produce drinking-water from a specific raw water source.

Typical processes employed include:

• Desalinization
• filtration
• softening
• disinfection or sanitization (e.g. by sodium hypochlorite)
• iron (ferrous) removal;
• precipitation
• reduction of concentration of specific inorganic and/or organic
materials

DW should be monitored routinely (consider seasonality)

Trend review may be used to identify chan - the storage
systems must not allow degradation of the water quality
5. Water purification systems

Production of purified water (PW)

The following should be considered:

• the feed-water quality and its variation over seasons;

• quantity of water required by the user;
• water-quality specification (USP)
• appropriately located sampling points
• Unit process steps should be provided with appropriate instrumentation to measure parameters:
 Flow
 pressure,
 Temperature
 Conductivity
 total organic carbon (TOC).

Ambient-temperature systems are especially susceptible to microbiological contamination, particularly when equipment
is static during periods of no or low demand for water.
It is essential to consider the mechanisms for microbiological control and sanitization.
The method for sanitizing each stage of purification needs to be defined. There should be document evidence
The following should be considered:
– maintenance of minimum flow through the water generation
system is recommended at all times;
5. Water purification systems

Production of purified water (PW)

The following should be considered:

• maintenance
• control of temperature in the system
• 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 peracetic acid)
• thermal sanitization at > 65 °C.
5. Water purification systems

Production of water for injection(WFI)

Distillation is the preferred

The following should be considered :

• the feed-water quality

• the required water quality specification
• the quantity of water

The storage and distribution system should be considered as a key part of

the system.

The storage and distribution system should be configured to prevent

microbial proliferation and recontamination of the water (PW, BHPW, BWFI).
It should be subjected to a combination of online and offline monitoring to ensure that the appropriate water specification is
maintained
6. Water storage and distribution systems

Production of water for injection(s)

pipework, valves and fittings, seals, diaphragms and

instruments, should be selected to satisfy the following
objectives.

■ Compatibility. - working temperature and potential

chemicals that will come into contact with the system at
rest, in operation and during sanitization.

■ Prevention of leakage. 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, BHPW and BWFI are highly

corrosive.

When stainless steel is used it should be at least grade 316.

In general 316L or a higher grade of stainless steel is used.
6. Water storage and distribution systems

Production of water for injection(s)

The system should be passivated after initial installation or after significant

modification.

Smooth internal surfaces help to avoid roughness that can be the source of contamination because of possible
accumulation of microorganisms and formation of biofilms.
6. Water storage and distribution systems

Production of water for injection(s)

• The internal material finish should have an arithmetical average surface roughness of not
• greater than 0.8 micrometre (Ra).
• When stainless steel is used, mechanical and electro-polishing techniques may be employed.
• ■ Jointing. welding in a controlled manner.:
• qualification of the operator
• documentation of the welder set-up
• work session test pieces (coupons)
• logs of all welds and visual inspection of a defined proportion of welds, e.g. 100% hand welds, 10% automatic welds.
• ■ Design of protuberances, unions and valves. unions or valves are used they should be of a hygienic or sanitary design.
Appropriate checks should be carried out to ensure that the correct seals and diaphragms are used and that they are fitted
and tightened correctly.
• ■ Documentation. All system components should be fully documented and be supported by original or certified copies of
material certificates.
• ■ Materials. Suitable materials that may be considered for sanitary elements of the system include 316L (low carbon)
stainless steel, polypropylene, polyvinylidene-difluoride and perfluoroalkoxy. The
7. Operational considerations

Qualification

should follow the validation convention of design

review or design qualification
(DQ), IQ, OQ, and PQ.

• Tests on the source water must be included within

the validation
• The source water should meet the requirements for ■ Sample or continuously monitor the incoming
drinking-water and any internal specification. feed-water daily to verify its quality.
■ Sample or continuously monitor after each
Phase 1. Sample daily the incoming feed-water to step in the purification process.
verify its quality. ■ Sample or continuously monitor at each point
of use and at other defined sample points.
A test period of two weeks should be spent monitoring
■ Develop and finalize operating, cleaning,
the system sanitizing and maintenance procedures (SOPs)
intensively. ■ Use and refine the standard operating
System should operate continuously without failure or procedures (SOPs) for operation, maintenance,
performance deviation. Usually water is not used for sanitization and troubleshooting.
finished pharmaceutical product. ■ Verify provisional alert levels.
■ Develop and refine test-failure procedure.
7. Operational considerations

Qualification

Phase 2.
A further test period of two weeks should be spent carrying
out further intensive monitoring while deploying all the refined SOPs after the
satisfactory completion of phase 1. :
– demonstrate consistent operation within established ranges;
– demonstrate consistent production and delivery of water of the required quantity
and quality when the system is operated in
accordance with the SOPs.

Phase 3. one year after the satisfactory completion of phase 2.

Water can be used for FFP manufacturing purposes during this phase which has the
following objectives:
■ to demonstrate reliable performance over an extended period;
■ to ensure that seasonal variations are evaluated.

The sample locations, sampling frequencies and tests should be reduced to the normal
routine pattern based on established procedures proven during phases 1 and 2.
7. Operational considerations

Continuous system monitoring

• A routine monitoring plan should be established based on the results of phase 3.

• Parameters:
• Flow
• Pressure
• Temperature
• Conductivity
• Total organic carbon (TOC) – online
• Offline:
• sample testing for physical, chemical and microbiological attributes.
• Offline samples should be taken from points of use
• All water samples should be taken using the same methodology as detailed in production procedures.

Monitoring data should be subject to trend analysis (trending should typically be within 2 sigma).
Suitable alert and action levels should be established based on historical reported data.

Any trend towards frequently exceeding alert limits should trigger a thorough investigation of the root cause, followed by
appropriate corrective actions.
 Dr. Francisco J. Eguiguren

[email protected]

00 593 993430604 Quito - Ecuador