®

standards

Implementing the ASTM standard

for verification (commissioning
and qualification)
Standard’s key objective is to give industry-wide flexibility
regarding implementation
By Steve Wisniewski and Chuck Stock, Integrated Project Services

R egulations have long required pharmaceutical

and biopharmaceutical manufacturers to validate
manufacturing processes, demonstrate control of
manufacturing environments, and control contamination.
In the United States, this mandate falls under the Code of Federal
Regulations (21 CFR Parts 210 and 211). In 1998, the International
Society for Pharmaceutical Engineering (ISPE) initiated an effort to
Navigating the process can be complex from the perspective of both
engineering and project management. It requires a bit of a paradigm
shift in management philosophy. Most companies will have to expand
their project teams in order to leverage the product knowledge obtained
by applying ICH Q8 and implementing a science- and risk-based
approach by applying ICH Q9. The additional effort and resources,
however, can not only facilitate regulatory compliance but can deliver
develop its Commissioning and Qualification Baseline Guide to help additional benefits for the facility owner.
manufacturers focus and prioritize their qualification efforts using the
risk assessment tool of impact assessment. More recently, a task team Balancing cost, efficiency, quality, and safety
formed through ISPE worked with the American Society of Testing and ISPE initially developed its C&Q baseline guide to lay out engineering
Materials (ASTM) committee E55.03 on a new consensus-based standard, approaches and practices that would help owners design and validate
Standard Guide for the Specification, Design, and Verification of
Pharmaceutical and Biopharmaceutical Manufacturing Systems
and Equipment. The standard (ASTM E2500) was voted upon and
Although participation by the
approved at the end of May.
Although participation by the U.S. Food and Drug Administration
(FDA) in ASTM Committee E55 and FDA’s affirmative vote of the stan-
FDA in ASTM Committee E55
dard do not constitute adoption, it points toward the agency’s support
for the new standard, which aligns with FDA’s published cGMPs. Further-
more, the National Technology Transfer and Advancement Act (NTTAA)
and FDA’s affirmative vote of
and OMB Circular A-119 on Federal Participation in the Development of
Voluntary Consensus Standards and in Conformity Assessment Activities
both direct agencies such as the FDA to use voluntary consensus stan-
the standard do not constitute
dards in lieu of government-unique standards whenever possible.
The standard provides high-level guidance—it explains what
needs to be done but not how. The specifics of that will be addressed
adoption, it points to the agency’s
in an updated ISPE baseline guide. A task team is in place, and its goal
is to have a revised draft of the guide available for ISPE membership
review in time for ISPE’s annual meeting in November. Although the
support for the new standard.
process is generally the same for everyone, how organizations choose to cost-effective manufacturing facilities that meet their intended purposes
implement the standard will vary depending on their quality goals, time in a timely manner. Its goals are to bring common terminology and
and cost requirements, and even internal roles and responsibilities. methodology to all involved in the C&Q process, to provide a system

Reprinted with revisions to format, from the October 2007 edition of CLEANROOMS
Copyright 2007 by PennWell Corporation
standards

impact assessment process, foster an interdisciplinary team approach, Figure 1: Good engineering practice
and establish a basis for planning and execution. It aims to eliminate
such costly practices as repeating verification steps during qualification,
Verification
qualifying systems that only require commissioning, and optimizing Requirement

documentation levels. The guidelines also are designed to help minimize

the project schedule and eliminate costly delays.
Built on the key concepts of good engineering practice (GEP),
impact assessment, and qualification practices, the baseline guide ad-
Product knowledge Operation
dresses the process of designing, constructing, commissioning, and Process knowledge
Regulator
Regulatory
qualifying facilities, utilities, and equipment regulated by the FDA or Company qualit
quality
other health authorities. The document positions commissioning and
qualification activities as the foundation for process validation. In fact,
Specification and design
a well conceived and executed commissioning and qualification plan Acceptance and release
greatly facilitates a timely, cost-effective validation effort. The document Risk management
also recognizes that taking a comprehensive approach to commission-
ing and qualification plays a critical role in delivering effective, safe, Design review
and efficient facilities, utilities, and equipment.
A comprehensive approach requires assessing each system for its Change management

potential impact on the product quality and patient safety. At one end of
the spectrum, parking facilities have no impact; at the other, the water
for injection (WFI) or U.S. Pharmacopeia (USP) water system clearly biopharmaceutical
z0709CRtech3Fig.1 manufacturing capability, from the actual
has a direct impact. The gray areas are systems such as air conditioning, manufacturing systems, equipment, and automation systems; it can
chilled water, or building management, which may have an indirect also be applied to laboratory and information systems. It applies to new
impact, depending on how they are designed and used. If the systems manufacturing systems and may be used when implementing changes
have no impact or only indirect impact, following GEPs should be and improvements to existing systems and equipment. Finally, the
sufficient. For systems with direct impact, it is necessary to make impact standard is applicable throughout the product life cycle, from concept
assessments at the component level to determine which components are to retirement.
critical. For example, if the HVAC system will have a direct impact, a In effect, this is the same basic scope of activities that compliance
component assessment might determine that only specific elements— professionals in the industry have addressed for the past 30 years but in
the main and terminal HEPA filters and the sensors for temperature, a new, more flexible package that allows the pharmaceutical company
differential pressure, and humidity—are likely to have an impact and to determine the methodology. The standard uses new terminology and
are therefore critical. Components identified as critical will require better defines current terminology, reflecting the science- and risk-
qualification. The quality assurance unit must endorse the rationales to based approach, and it puts the quality team and technical experts in
support these assessments. new roles.
One of the major differences is the concept of verification. Under
ASTM verification: A risk- and science-based approach the ASTM standard, the company should define a systematic approach
The ASTM verification standard takes the ISPE baseline to the next to verify that the manufacturing elements—individually and in
level. The standard describes a risk- and science-based based approach combination—are fit for intended use, have been properly installed,
to specifying, designing, and verifying elements of a manufacturing and operate correctly. The company must document the verification
capability to ensure that those systems and equipment are fit for intended approaches used, providing a level of detail appropriate to the level of risk
use, and that product quality risks related to those manufacturing to product quality and patient safety, as well as the complexity and novelty
elements are managed effectively. Ultimately, the manufacturing of the approach. Traditional installation and operational qualification
capability should be able to support defined and controlled processes that protocols can be set aside in favor of documented confirmation by SMEs
consistently produce a product that meets defined quality requirements. that all acceptance criteria have been met. This documentation should
The standard applies a number of key concepts including a risk-based include a review or overview of results, as well as a review of any non-
approach as provided by ICH Q9, Quality Risk Management; and a conformance to acceptance criteria and corrective actions taken. The
science-based approach and quality by design, as provided by ICH Q8. It documentation should clearly state whether the manufacturing system
applies the concept of critical quality attributes and calls for the use of or equipment is fit for intended use.
subject matter experts (SMEs) to make critical determinations. Like the In contrast to the traditional qualification process, the verification
ISPE guidance, it acknowledges that GEPs may be sufficient for certain approach requires that the quality unit shift its emphasis from quality
systems. It also seeks to minimize the paperwork burden by allowing for control to quality assurance. Where previously the quality unit was
the use of vendor documentation. involved in every protocol test case, every minor discrepancy, and
The standard applies to all elements of pharmaceutical and endless wordsmithing to justify minor departures from engineering
 standards

specifications, under the ASTM standard, the responsibility for unit should approve the acceptance criteria. The SMEs also should
engineering quality control falls on the technical experts with appropriate develop and approve the verification plan and specifications, including
oversight by quality assurance. Non-critical discrepancies are addressed the method of verification and test strategy. Finally, the SMEs should
through GEPs. Instead of an obsessive focus on documenting every perform the verification activities as defined, document the results, and
minor detail, the team can now focus its documentation practices on document that verification activities have been completed. The ASTM
technical content—a far more efficient approach. standard allows for the use of vendor verification documentation.
An independent technical reviewer with the appropriate back-
A new process paradigm ground, knowledge, and familiarity with the technical aspects of the
The move to the ASTM verification standard requires a new approach manufacturing elements should review all completed verification docu-
to the specification, design, and verification process, moving away mentation, ensuring that all tests have been completed and appropriate-
from the “V Model” of commissioning and qualification. The new ly documented. The technical reviewer and SMEs should work together
paradigm demands that the principles of good engineering practice, to address and resolve any departures from the verification plans and
risk management, design review, and change management are applied specifications.
at each stage of the process, from compiling design requirements to
acceptance and release and beyond. From impact assessment to risk assessment
The keys to success under the ASTM standard are in upfront plan- Another paradigm shift that the ASTM standard brings about is the
ning and interdisciplinary communication. Goals and objectives must be approach to risk assessment. Since the ISPE baseline guide was
clearly defined, because they will drive the process and impact everything introduced, companies have relied primarily on impact assessment—
downstream. Accurate, well thought-out input into the requirements is that is, evaluating the impact of the operating, controlling, alarming,
critical. The requirements should be based on knowledge of the product and failure conditions of a system on the quality of the product.
and its manufacturing process, as well as regulatory requirements and Impact assessment is a labor-intensive process that focuses on systems
the company’s own quality requirements. Available product and process and components and usually is conducted after design development.
knowledge can be determined by reviewing the scientific data gathered Under the ASTM standard, impact assessment is just one of many tools,
during experimental and development work. This information can pro- including hazard operability analysis (HAZOP), failure mode effects
vide the basis for specific product/process requirements relevant to prod- analysis (FMEA), and fault tree analysis (FTA) that can be applied to
uct quality and patient safety. Specification and design activities should the process.
focus on those aspects that have been identified as critical to product Risk assessment is performed throughout the design development
quality and patient safety. Subject matter experts should be the ones to ensure that the systems and other facets of the design and operat-
to identify and document these critical quality attributes—functions, ing philosophy can effectively monitor and control risks to the manu-
features, abilities, and performance or quality characteristics—that are facturing process, such as process variability and contamination. Each
necessary to consistently produce products of the required quality. The selected process is assessed against a set of product and process user
requirements. The risk management requirements include all compo-
nents, functions, and features that serve, collectively or individually, to
The standard uses new control risk. These are designated as critical elements. The risk assess-
ment should determine the probability that any specific risk could im-
pact process variation and the degree to which that impact could affect
terminology and better defines product quality and safety. Risks that are deemed unacceptable are to be
eliminated by design, automated control, or procedural controls. Com-
panies will find more specific details on risk management in ICH Q9.
current terminology, reflecting When verifying manufacturing systems and equipment, the
procedure should be documented in sufficient detail that trained
individuals can repeat the test in the same manner and obtain the same
the science- and risk-based results. Similarly, the observed results should be documented adequately,
so that a technically competent person can verify that the inspection
or test was performed properly and that the acceptance criteria were
approach. met. An independent SME should review the results to ensure that all
tests were completed, acceptance criteria met, and all appropriately
company should have a systematic means of conveying these specifica- documented. Documentation should also include confirmation that
tions to those responsible for design so that manufacturing systems and any departures from specification have been addressed through GEPs or
equipment are properly designed to meet relevant requirements. change control for nonconformance. Depending on the circumstances,
Subject matter experts also should define the acceptance criteria the process of verification may or may not include performance testing.
that must be satisfied in order to demonstrate that manufacturing At the conclusion of verification, the subject matter expert will document
systems and equipment meet the critical quality attributes. The quality the results of the verification effort in a verification report. The quality
standards

unit, and possibly other technical experts, will challenge have run the gamut from equating experience in the pharmaceutical, biotechnology, and
approve the verification summary report. commissioning with qualification—a costly, device industries, including senior management roles
laborious, and time-consuming tactic—to at Sterling Winthrop and Bausch & Lomb. He currently
Conclusion eliminating any commissioning and going serves as chairman of the ISPE Community of Practice
Pharmaceutical and biopharmaceutical com- right to validation—a course of action that is for Commissioning and Qualification, and serves on the
panies are challenged to develop manufactur- often fraught with failure. ISPE Task Teams for developing the ASTM verification
To determine the best approach for standard and the revised C&Q baseline guide.
implementing the ASTM verification standard,
This phased approach the company will need to explore its goals for Chuck Stock is senior vice president and principal in
the process. Does the system need to improve charge–compliance for IPS. He has more than 25 years
can help the company compliance? Enhance product quality? Provide
greater contamination control? Minimize
of management-level experience in process, operations,
and compliance in the pharmaceutical, biotechnology,
capital costs? Initially, it may be helpful to and device industries. Stock has successfully started
obtain the desired find an expert who is experienced with this up, commissioned, and validated cell culture facilities,
verification process to create an approach plan vaccine facilities, oral solids and liquids facilities, and
outcomes from its and preliminary schedule and then develop
a detailed list of activities to determine the
bulk chemical and device facilities. He has developed
and presented training programs and seminars for
project scope. Once that detailed foundation cGMPs, validation, project management, and master
chosen approach has been laid, the request for proposal can planning to U.S. and international industry groups
include a list of expected deliverables to ensure and individual companies. He currently is team leader

to verification/ that potential vendors are bidding “apples to

apples.” This phased approach can help save
for Expert Consultants in a Consent Decree for quality
system elements.
time and money and help the company obtain
qualification under the the desired outcomes from its chosen approach References
to verification/qualification under the ASTM 1. ASTM International, New Standard Guide to a

ASTM standard. standard. Science and Risk-Based Approach to Qualification

of Biopharmaceutical and Pharmaceutical
Steve Wisniewski is senior associate and director of Manufacturing Systems, 2007.
ing capability quickly and cost effectively while compliance for Integrated Project Services (IPS), a full- 2. International Society for Pharmaceutical Engineer-
safeguarding product quality and patient service engineering firm specializing in the delivery of ing, ISPE Baseline® Guide: Commissioning and
safety. To date, approaches to meeting that technical complex projects. He has more than 30 years’ Qualification, March 1, 2001.

Integrated Project Services (IPS)

2001 Joshua Road
Lafayette Hill, PA 19444
T: 610.828.4090
F: 610.828.3656
www.ipsdb.com