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ASTM Standard E 2500 for Specification,

Design and verification of Pharmaceutical and

Biopharmaceutical Manufacturing Systems &

Presentation by
Sasidharan S Menon
Subject Matter Expert (SME) Design and Evaluation
Controlled Environments for Contamination Control

Why change our work cultures and

regulatory framework to move from
traditional Qualification approach to
Value added model?
A maximally efficient, agile, flexible
pharmaceutical manufacturing sector that
reliably produces high quality drug products
without excessive regulatory oversight.
-Ms Janet Woodcock, MD

Were we working under the delusion

of Quality by Accident before?
Quality Risk Management (QRM) is critical in development of
the product Quality Control strategy.
An understanding of the product and process in terms of
fundamental, mechanistic properties as opposed to empirical
(based on observation and experience rather than theory or
Utilization of prior knowledge in defining the product,
process and facility.
Facility designed to accommodate the products life cycle.
Risk analysis, Risk assessment, Risk Management.

International Conference on Harmonization


Pharma Dev.

Pharma Quality
Quality Risk Mgmt.

Q8 Pharma development
Collecting the knowledge needed.

Q9 Risk Management
Application to our needs using the knowledge.

Q10 The Enablers

The Maintenance of our product, process and facility through
the lifecycle of the product.

ICH Q9 Quality Risk Management

(QRM) was published in 2005 and
differentiates Commissioning and
Traditional method IQ, OQ, PQ (Installation
Qualification, Operational Qualification, Performance
Qualification), one followed by next step, mostly
treated as quality/regulatory functions.
Current Risk based approach ISPE Baseline Vol 5
advocates Impact assessment, GEP (Good Engineering
Practice), Commissioning concurrent with IQ/OQ and
gives leverage to Commissioning.

Latest ASTM E 2500 ISPE Baseline

Volume 12

Verification Vs Qualification

Engineering change management

QA change control

Original C&Q
Volume 5

Enhanced design





Design for impact

Scope of Guide

Engineering change management

Volume 12

QA change control
Design review

Verification testing



Volume 12 Rationale for the new

Presents a structured lifecycle approach to the delivery of
facilities, systems and equipment which support these regulatory
Designed to improve the way in which the industry delivers
regulated manufacturing capacity
Improve the ability to meet documented process requirements
Control risks within the manufacturing process
Produce high quality products which consistently operate to
meet product user requirements.

Volume 12 Baseline Guide describes the Principles required when

applying a science and risk based program.

Verification The New Approach

A systematic approach should be defined to verify that
manufacturing requirements, acting singly or in
combination, are fit for intended use, have been properly
installed, and operating correctly.
This verification approach should be documented.
The extent of verification and the level of detail of
documentation should be based on risk to product quality
and patient safety, complexity, and novelty of the
manufacturing system.

Qualification Vs Verification Old Vs

Old: Qualification consists of a series of IQ, OQ, and PQ

New: Subject Matter Experts should confirm that all Acceptance

Criteria have been met and that the equipment systems are fit
for use. This confirmation should be documented.
Such documentation should include a review or overview of the
results, and a review of any non-conformance to acceptance
criteria. There should be a clear statement as to whether or not
the manufacturing requirements are fit for intended use.

Risk Assessment Old Vs. New


Impact Assessment: the process for evaluating the impact

of the operating, controlling, alarming, and failure
conditions of a system on the quality of the product
Conducted after design development
System and component level focused not
Labor intensive process

Risk Assessment Old Vs. New


An assessment of the chosen process design against a set

of approved product and process user requirements.
Performed throughout design development to assure the
collection of systems and other facets of the design and
operating philosophy are capable of monitoring and
controlling risks to the manufacturing process, including
control of process variability, control of contamination, etc.
(linked to the identified CQAs and CPPs)
The risk management requirements identified are
designated as critical and include all components, functions
and features of the design that serve, collectively or singly,
to control risks.

Risk Assessment Old Vs. New

Risks are evaluated as to their probability and severity
to determine the impact to process variation and effect
on product quality and safety.
Unacceptable risks are mitigated following the preferred
hierarchy of:

Elimination by Design
Elimination by Automated Control
Elimination by Procedural Controls

Role of Design/Engineering:
Clearly define design/engineering phases
Risk assessment becomes an integral part of design phase
Basis of design : Design development
Critical Process Parameters

Design review
C & Q Master plan
Vendors/Contractors producing design documents
Who is in control?
Documentation management

ASTM standard E 2500

ASTM Standard E 2500 for Specification, Design and
verification of Pharmaceutical and Biopharmaceutical
Manufacturing Systems & Equipment
The new ASTM standard provides a science and risk
based approach to assure that GMP equipment and
systems are:
Fit for use
Perform satisfactorily
May be used in the manufacturing, processing, packaging
and holding of a drug or therapeutic agent.

Key Concepts
Good Engineering Practice (GEP):

Good Engineering practice should underpin and support the

specification, design and verification activities.

Subject Matter Experts (SMEs):

Subject Matter Experts are defined as those individuals with
specific expertise in a particular area or field.
SME responsibilities include planning and defining
verification strategies, defining acceptance criteria, selection
of appropriate test methods and execution of verification tests
using different vendors and reviewing results.

Key Concepts

Use of Vendor Documentation

Vendor documentation, including test documents may be
used as part of the verification documentation, provided
the regulated company has assessed the vendor, and has
evidence of:

An acceptable vendor quality system

Vendor technical capability
Vendor application of Good Engineering Practice

Key Concepts
Use of Vendor Documentation
If inadequacies are found in the vendors quality systems,
technical capability, or application of GEP, then the user or
SME may choose to mitigate potential risks by applying
specific, targeted, additional verification checks or other
controls rather than simply repeating vendor activities and
replicating vendor documentation.

The decision and justification to use vendors

documentation to support the verification of CQAs, should
be based on the intended use of the manufacturing
element, and should be documented and approved by
SMEs and quality unit.

Key Concepts
Quality by Design
To ensure that quality attributes and requirements are
designed-in during the specification and design process.
Pre tender meeting of prospective vendors are important
to inculcate user requirements and expected quality
Assurance that all systems are fit for purpose and not
relying solely on verification after installation, but be
achieved by a planned and structured verification
approach applied throughout the systems life cycle.

Process Verification review

All completed verification documentation should be
reviewed by suitable qualified and independent SME(s),
who did not execute the verification tests.
The reviewers should ensure that all tests have been
completed and appropriately documented.
Departures and deviations from verification plans should
be discussed and resolved by the reviewer and/or SMEs.

Process Acceptance and release

SMEs should confirm that manufacturing system is fit for
intended use and such confirmation should be
Such documentation should include a review or overview of
the results, and a review of any non-compliance of critical
aspects. The person/s involved in making this
determination should be identified and documented.
Such documentation should be prepared and approved by
SMEs, and be approved by the quality unit.

Following the approvals, the manufacturing systems may

be released for operational use.

Be Aware
Understanding of the product, process, manufacturing
steps and facilities is critical.
Early agreement between Management, Engineering,
Quality & other stake holders is essential before moving
in new direction.
Clear understanding of Engineering Documentation is
Identification of SMEs is of utmost importance.

Commissioning should include the setting up, balancing,

adjustment and testing of the entire HVAC system, to
ensure that it meets all the requirements, as specified in
the user requirement specification (URS), and capacities
as specified by the designer or developer.
The installation records of the system should provide
documented evidence of all measured capacities of the
Acceptance criteria should be set for all system
parameters. The measured data should fall within the
acceptance criteria

Acceptable tolerances for all system parameters should

be specified prior to commencing the physical

Training should be provided to personnel after

installation of the system, and should include operation
and maintenance.

Commissioning should be a precursor to system

qualification and process validation.

Validation is a many-faceted and extensive activity and is

beyond the scope of these guidelines.
Qualification and validation guidelines are included in:
Expert Committee on Specifications for Pharmaceutical
Fortieth report. Geneva, World Health
Organization, 2005 (WHO Technical Report Series, No.
937), Annex 4.
A risk-based approach should be used to identify the
extent to which the HVAC system requires qualification
and verification.

Any parameter that may affect the quality of the

pharmaceutical product, or a direct impact
component, should be considered a critical parameter.
All critical parameters should be included in the
qualification process.

Note: A realistic approach to differentiating

between critical and non-critical parameters is
required, to avoid making the validation process
unnecessarily complex.

The humidity of the room where the product is exposed

should be considered a critical parameter when a
humidity-sensitive product is being manufactured. The
humidity sensors and the humidity monitoring system
should, therefore, be qualified. The heat transfer system,
chemical drier or steam humidifier, which is producing the
humidity controlled air, is further removed from the
product and may not require operational qualification.

A room cleanliness condition is a critical parameter

and, therefore, the room air change rates and HEPA filters
should be critical parameters and require qualification.
Items such as the fan generating the airflow and the
primary and secondary filters are non-critical parameters,
and may not require operational qualification.

Non-critical systems and components should be subject to

GEP and may not necessarily require qualification.
A change control procedure should be followed when
changes are planned to the direct impact HVAC system,
its components and controls that may affect critical
Out-of-limit results (e.g. action limit deviations) should
be recorded and their impact should be investigated.
The design condition, normal operating ranges, operating
range and alert and action limits should be defined and
be realistic.

To conclude, for a pharmaceutical facility, based on a risk

assessment, some of the typical HVAC system parameters that
should be qualified may include:
Relative humidity
Supply air quantities for all diffusers
Return air or exhaust air quantities
Room air change rates
Room pressures (pressure differentials)
Room airflow patterns
Unidirectional flow velocities
Containment system velocities
HEPA filter penetration tests
Room particle counts
Room clean-up rates
Microbiological air and surface counts where appropriate