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Biopharmaceuticals

The following Reprinted from The Official Journal of ISPE


Executive PHARMACEUTICAL ENGINEERING March/April 2003, Vol. 23 No. 2

Summary
represents the
draft of the ISPE
ISPE Baseline Pharmaceutical Engineering Guide For
Biopharmaceuticals New and Renovated Facilities Volume 6:
Baseline Guide
that has been Biopharmaceuticals - Executive
available to FDA
and ISPE
members for
Summary
comment, with
comments due to Table of Contents 3.1 Executive Summary
ISPE by March 1 Introduction 3.2 Open Versus Closed Systems
2003. 1.1 Background 3.3 Pyrogen-Controlled Processing
1.2 Scope of The Guide 3.4 Considerations For Multi-Product Op-
1.3 Key Concepts of the Guide erations
It is likely that 1.4 Using the Guide 3.5 Viral Clearance
parts of this 2 The Regulatory Basis for Facility Re- 3.6 Stage of Product Development
summary will quirements 3.7 Operational Upset
change to reflect 2.1 Executive Summary 3.8 Operability and Maintainability
2.2 Scope 3.9 Cleaning and Housekeeping Consider-
these comments, 2.3 Definitions ations
and therefore the 2.4 Regulatory Considerations 4 Chapter 4: Process And Equipment
summary should 2.5 General Concepts 4.1 Executive Summary
be considered 2.6 Bibliography 4.2 Typical Biopharmaceutical Processes
2.7 Significant Regulatory Documents 4.3 Critical Process Parameters
only a general 3 Manufacturing Operations and Activi- 4.4 General Considerations for Equipment
indicator of the ties Design
topics covered in
the Baseline
Guide.

Figure 1. Proposed
structure of the final
ISPE Baseline Guide for
Biopharmaceuticals.

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4.5 Specific Equipment Design Con- Solutions are applied out of context Drug Evaluation and Research
siderations (one products approaches inappro- (CDER).
4.6 Summary priately applied to a different type US GMPs:
5 Process Support and Utilities of product) Not much is specifically stated in the
5.1 Executive Summary Product and process are not consid- US GMPs, but best practices are
5.2 Regulatory Issues ered in decisions. A common reason is covered here. It is ultimately the
5.3 System Impact Descriptions Company X did it, so we should, too. owners responsibility to justify deci-
5.4 System Layout and Routing Capital concerns: sions and approaches to regulators.
5.5 Specific Service Considerations Capital funds may be limited, so Other GMPs are covered in the Appen-
6 Facility wise use of funds is important dix. National Institute of Health (NIH)
6.1 Executive Summary The need to get quick facility ap- and other safety issues are mentioned
6.2 Process Considerations proval at all costs has led to over- in the Guide where they affect GMPs or
6.3 Operational Considerations spending to remove potential snags design.
6.4 Facility Layout Considerations during inspections The audience for this Guide is pro-
6.5 Operational Support Money is not going toward product fessionals involved in the design, con-
6.6 Area Environment protection as much as to fluff: struction, validation, and operation of
6.7 Architecture And Finishes Money that could have been used licensed biopharmaceutical manufac-
6.8 Discretionary Considerations for protecting the product is diverted turing facilities.
7 Process Controls to features with no product impact: The mission of the Baseline Guides
7.1 Executive Summary - Mirror finishes, stainless steel is to help operating companies sat-
7.2 Biopharmaceutical Automation facilities isfy the GMPs and produce product
Issues - Confusion regarding required in a manner that allows the manu-
7.3 Level of Automation process water quality, often over- facturer to stay in business.
7.4 Biopharmaceutical Unit Opera- specified without economic or sci- This Guide is not a GMP, but in-
tions entific justification stead it focuses on the use of re-
7.5 Control Systems Maintenance - Classified spaces (cleanrooms) sources to meet GMP. This Guide is
7.6 Validation of Biopharmaceutical where they are not needed, as for but one approach to satisfying the
Automation Systems closed processes intent of the GMPs. Other methods
8 Commissioning and Qualifica- of protecting the product may exist
tion 1.2 Scope of the Guide now or evolve in the future. If an
8.1 Executive Summary This Guide may be used by industry for issue is not covered in this Guide, or
8.2 Impact Assessment the design, construction, commission- if alternatives appear feasible, the
8.3 Qualification ing, and qualification of new and reno- reader is advised to discuss them
9 Glossary vated biopharmaceutical facilities. It with the appropriate regulatory
10 Appendix - European Aspects is neither a standard nor a GMP, nor is agencies before significant finan-
10.1 Introduction (General) it a detailed design guide. It is not cial commitments are made.
10.2 Water Quality (Ref: Chapter 4 intended to replace governing laws or It is intended that this Guide will be
And 5) regulations that apply to facilities of used by regulators and quality con-
10.3 Bio-Containment and Environ- this type. The application of this docu- trol personnel to understand the tech-
mental Protection (See Chapter 5) ment for new or existing facilities is at nical issues regarding the facility or
10.4 Environmental Impact Issues the discretion of the facility owner or process. This Guide does not attempt
10.5 Chromatography Skid Sharing operator. Approaches to meeting GMP to cover the basics of the engineering
10.6 Qualification and Validation provided in this Guide need not be sciences, nor does it attempt to cover
(Ref: Chapter 8) retroactively applied to currently li- biopharmaceutical GMPs that do not
censed facilities. address the facility or the manufac-
1. Introduction This Guide applies to large mol- turing process technology.
1.1 Background ecule biotech products, cell-cultured,
The design, construction, commission- or fermented: 1.3 Key Concepts of the Guide
ing, and qualification of biophar- It does not apply to blood, vaccines, 1.3.1 Does the Process Equal
maceutical facilities will challenge etc. However, most concepts in this Product?
manufacturers, engineering profes- Guide may be applied to these prod- There is a continuum of process and
sionals, and equipment suppliers. ucts. facility approaches based on the prod-
These facilities must not only meet It applies to biopharmaceutical Ac- uct and processes used to make the
cGMP regulations, but must comply tive Pharmaceutical Ingredient product. The best engineering solution
with local codes, laws, and regulations. (API) products licensed by both the makes optimal use of people, materials,
The current situation is one of con- Center for Biologics Evaluation and and capital while protecting the prod-
fusion and sometimes little science: Research (CBER) and Center for uct. There is not one right or perfect

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way to design and operate the facility. well as viral clearance and clinical 1.3.3.2 The Process Cannot
However, the design of a facility has a materials manufacture. Add Contamination
profound impact on process design and Process controls: The processs contamination profile
on how the facility is operated. Automation is not a GMP require- must be known and the process con-
Due to limitations in analytical meth- ment, but if automation is used, trolled to specifications.
odologies and only superficial under- then there are GMP implications. Process Water should reflect the
standings of the relationships between Chapter 7 provides more insight product purity profile.
process variables and final product qual- regarding automation. Chapter 3 discusses recovery from
ity, biopharmaceutical processes have For subjects generic to all pharmaceu- upsets and prevention of contami-
historically been viewed as black tical facilities, the reader is directed to nation in manufacturing operations.
boxes. Thus, there also has been a other sources for more in-depth infor-
prevailing view that the process equals mation. 1.3.3.3 Contamination Control
the product. This view has led to reluc- Qualification basics are covered in Strategy
tance to alter biophar-maceutical pro- the ISPE Baseline Guide for Com- As discussed in Chapter 3, bulk
cesses, a reluctance that has been rein- missioning and Qualification. biopharmaceutical manufacturing is
forced by conservative regulatory ap- - Commission everything in accor- low bioburden production. Aseptic-
proaches. How could manufacturers dance with Good Engineering like processing steps or sterile pro-
assure the identity of the final product Practice, but qualify only direct cessing operations utilizing sterilized
in the case of process variations? How impact systems and critical com- process equipment are usually oper-
could manufacturers assure the final ponents of those systems. ated closed.
product with changes in scale or changes - Design Qualification or En- Chapter 3 also discusses housekeep-
in the facilities of manufacture? hanced Design Review will help ing, cleaning, and fumigation. Chapter
As the industry has developed a comply with ICH Q7A. 4 discusses equipment cleanability, and
better understanding of biophar- - Qualification considerations spe- closure.
maceutical processes and as analytical cific to Biopharmaceutical sys-
methods have improved, we have de- tems are covered in Chapter 8 1.3.4 Segregation and Flow
veloped a better understanding of the with reference to topic-specific Segregation protects the product from
cause and effect relationship between qualification activities in Chap- contamination in its surroundings (i.e.,
process variables and products. This ters 3 through 7. from the facility and other products).
evolution has caused a change in focus Water and steam systems are cov- Segregation may be accomplished via
to those issues that are critical to the ered in the ISPE Baseline Guide procedures, timing, or by physical
consistent manufacture of high quality for Water and Steam Systems. means. Flow patterns in the facility
products. Products and processes have The Guide user is encouraged to work influence segregation, especially if more
been proven to be transportable be- with the regulators to iron out unique than one product is manufactured
tween facilities and can be operated on issues before they become significant there. Chapter 6 provides more detail
different scales. issues. to help decision-making regarding seg-
regation and flow.
1.3.2 Process Design is Tied 1.3.3 Controlled Processing Primary and secondary segregation:
to Facility Design The product must be protected by con- As discussed in Chapters 2, 3, and 6,
This Guide covers the variables that trolling the process and often its sur- protection of product may be accom-
most directly affect the process and roundings. This requires knowledge of plished through primary and second-
facility: the product and process and protection ary segregation.
Open versus closed processing: utilizing segregation and flow patterns. Primary Segregation - used to
- Closed processing places more Chapter 3 discusses controlled process- mitigate a known risk of product con-
emphasis on protecting the prod- ing in more detail. tamination, usually supported by a
uct INSIDE the process. strong GMP driver and process data. It
- Open processing places more em- 1.3.3.1 Know the Product is the foundation of the basic organiza-
phasis on the facility and its (and its Process) tion and operation of the facility and
people. Intimate knowledge of the product, its identifies process steps at risk.
What works best for one product, critical parameters, the processes in- Secondary Segregation - used
facility, or process scale may not volved, and processing parameters is when there is little demonstrated risk
work best for another product, facil- essential. Evaluation of potential con- to product, but segregation is desirable
ity, or process scale. tamination routes is needed. Data that to minimize the risk of human error and
Features that work well in a single demonstrate control of the process and mix-ups. There is no direct impact on
product facility may be inadequate to justify processing decisions will be product quality, but it helps define the
for a multiple product facility. key to a successful facility. facility and its operation although more
Chapter 3 discusses these issues as from a management standpoint than

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intrinsic process protection. Secondary vide segregation, but to a lesser de- More portable equipment, often
segregation is open to interpretation as gree. The use of a hard definition shared with other products
to applications and methodology. may limit the understanding of More need for classified spaces
closed. Single product vs. multiple prod-
1.3.4.2 Flow and Traffic The surrounding room environment ucts manufacture
Patterns in the Facility is not part of the equation for a As discussed in Chapter 3, when more
Implementation of the segregation closed process, but it should be con- than one product is manufactured in a
strategies results in flow. trolled. facility, ensuring the products safety
Flow patterns should address scale, and quality becomes more difficult, but
volume, and duration of expected 1.3.5.2 If a unit operation is no less important. Multi-product manu-
traffic. open, the product must be facturing facilities may segregate prod-
Flow patterns also should address protected by other means. ucts by campaigning (one product at a
upset conditions (such as mainte- Open = not closed time) or may process multiple products
nance and change out of large equip- Product = process + facility concurrently.
ment) and future construction. Surrounding environment is a fac- Campaigning depends heavily on
A mature materials handling phi- tor in the process. validated cleaning and changeover
losophy must be in place before es- Either a classified space or a controlled procedures (Chapter 3).
tablishing flow patterns. non-classified environment will likely Concurrent manufacturing must avoid
be needed, but the need for area moni- cross-contamination through physical
Philosophies of primary and secondary toring is driven by the open process. segregation and operating procedures.
segregation affect flow patterns: The choice between closed process- (Chapters 3 and 6)
Raw Materials Flow ing in Controlled Non-Classified (CNC)
Product Flow, including intermedi- space and open processing in classified 1.4 Using the Guide
ates and hold points space is often driven by scale of the 1.4.1 Organization of the Guide
Personnel Flow process, cost of operations, and value of An overview of the Guides structure is
Glass and Equipment Flow (through product at risk. shown in Figure 1.
cleaning protocols) Chapter 4 provides information to
Waste Flow help in selecting process equipment to 1.4.2 Application of the Guide
Flow patterns may force issues with meet open or closed requirements. As shown in Figure 1, it is necessary to
the cleanliness of the facility: Chapter 6 discusses the effects of pro- begin by understanding the GMP re-
Materials of construction and archi- cess closure on the facility. quirements (Chapter 2) and then ad-
tectural details dressing the product and operational
Building layout and potential con- 1.3.6 Scale Affects Decisions requirements (Chapter 3). From there,
tamination routes (via air, people, Chapters 3, 4, and 5 deal with process once operational concepts have been
equipment) design and support utility design is- established, User Requirements de-
Issues with cleaning of equipment sues connected with process scale, and fined, and perhaps even a Functional
and piping: Chapter 6 covers facility layout op- Design created, the discipline design-
- CIP/SIP tions. ers may begin detail design.
- Wash Facilities One size does not fit all. As scale of Users of this Guide are advised to
the process increases, there is a shift refer to other ISPE Baseline Guides
1.3.5 Open toward: for more detailed or complementary
versus Closed Processing Vertical layouts with gravity flow of information. For example, water and
If a unit operation is demonstrated materials steam systems are thoroughly dis-
closed, it may operate in Controlled More closed operations cussed in the ISPE Baseline Guide for
Non-Classified (CNC) space. More Primary segregation Water and Steam Systems, and the
Closed - segregation by physical Equipment fixed in place (often dedi- design of classified pharmaceutical
means (hardware) to protect the cated) manufacturing space is discussed at
product and process from contami- More automation length in the ISPE Baseline Guide for
nation by the surrounding environ- Controlled non-classified space in- Sterile Manufacturing Facilities.
ment (outside the process) stead of classified space (due to Users of this Guide are also encour-
Closure and its measures must be closed processing) aged to understand GMP and specific
defined by the Owner, and demon- Small process scales tend to include: product requirements thoroughly be-
strated to prevent contamination of Horizontal process flow with pumps fore attempting facility design. Where
the product. Open operations there is conflict or a lack of under-
Various operating systems have Segregation by time (campaigning) standing, manufacturers and engineers
varying degrees of closure, some may Manual operations (mixing, etc.) are encouraged to discuss concepts with
be absolute, while others also pro- Less automation the appropriate regulatory agency.

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Such early discussion opens dialogue oped include: follows:
and helps to settle potentially thorny There is not one universal GMP Operational and Procedural
issues. standard or approach to biophar- Controls can play an important
maceutical facility and process de- role in protecting the product, and
2. The Regulatory Basis for sign. The nature of the product and must be factored into the open ver-
Facility Requirements its processes greatly influences these sus closed design decision. Appli-
During the design of new facilities, decisions. Systems and their com- cation of these types of controls with
every manufacturer faces numerous ponents will have varying effect on a well trained manufacturing staff
issues that may significantly affect the each product. can often be a better solution than
facility cost. These include process defi- Biotech manufacturing operations over-engineering a system.
nition, process equipment require- are not usually intended to produce Bioburden-Controlled Process-
ments, the definition of a suitable a sterile drug substance, but rather ing and Pyrogen (Endotoxin)-
manufacturing environmental quality one of low bioburden. Although the Controlled Processing are key
to support manufacturing, water re- voluntary adoption of aseptic manu- operational concepts that have a
quirements, and facility layout. While facturing techniques and facility significant impact on process and
some of the issues faced may affect the standards have occurred in the in- facility design, and both are dis-
quality of the Active Pharmaceutical dustry, such standards are not re- tinctly different from sterile pro-
Ingredient (API or bulk drug sub- quired. The production process and cessing. Some features of traditional
stance), others may have no impact. facility should include the appropri- sterile design and operation may be
The primary element to be consid- ate controls to prevent, limit, and employed, but are typically not re-
ered in a biopharmaceutical facility is detect API contamination. quired to establish the appropriate
the ability of the facility and the pro- Processes may be closed or open. level of control.
cess to protect, i.e., prevent contamina- Closed processing presents less risk Viral Clearance (Reduction and
tion of, the API. Product protection to product and presents fewer de- Inactivation) Biopharmaceutical
issues may be addressed in a voluntary mands on the facility design. Local processes commonly use raw mate-
Product Protection Control Strategy. controls may be used with open pro- rials from biological sources, start-
The evolution of facilities for manu- cesses to provide protection of the ing with the cell line and often ex-
facturing biopharmaceutical products product. tending to supplements added dur-
has led to many extremes in size, com- Multiple products segregated by ing the cell culture and purification
plexity, and capital/resources. Process- appropriate procedural or physical stages. Cell lines used in the bio-
ing approaches and designs suitable means may be produced within a technology industry are extensively
for a small-scale process are often in- single facility. characterized for identity and pu-
adequate or inappropriate for a large- Water used in manufacture should rity, and are tested for the presence
scale facility. The multi-product facil- be appropriate to the process; WFI of infectious agents. Nevertheless,
ity will differ in certain key areas from may not be scientifically necessary it is still a regulatory requirement
either of these dedicated facilities. throughout the entire process for for manufacturers using mamma-
Specifically, each company should most products. lian cell culture-based processes to
determine the appropriate require- demonstrate adequate viral clear-
ments to provide adequate protection 3. Manufacturing ance during the manufacturing pro-
for its product(s), and thereby, the re- Operations and Activities cess. In addition, increasing con-
quirements for the completed facility. This Chapter involves the operational cern over the transmission of prions
No single solution or design fits all aspects of a biopharmaceutical facil- from animal-sourced raw materials
drug substances or products since the ity, as opposed to the physical design of has required manufacturers to take
decisions made and incorporated in the facility itself, and addresses key additional measures to minimize the
the facility will depend upon: regulatory issues and concepts defined risk of such contamination. The de-
Nature of the process and product in Chapter 2. The Chapter addresses cision on how/where to accomplish
(i.e., contamination-sensitive pro- the impact of facility and equipment viral clearance can have an impact
cesses to less sensitive processes, design decisions on manufacturing op- on the equipment design, and may
open versus closed processing, etc.) erations. Conversely, the Chapter also affect the design and layout of the
Scale and complexity of the process describes how operability and main- facility.
Number and types of the products tainability considerations should in- Segregation is critical in any
in the facility fluence the design of a biophar- biopharmaceutical operation to en-
This Chapter addresses some of the maceutical facility. Concerns and is- sure product protection. Traditional
significant process-related concepts sues of production management, pro- applications include:
and facility attributes with regulatory cess operators, and other plant support - Between organisms, products, or
implications to be considered when personnel are included. Important con- technologies
designing a facility. Key points devel- cepts addressed in this Chapter are as - Between processing steps (e.g.,

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upstream and downstream op- biopharmaceutical process equipment, are identified for typical unit opera-
erations) and associated piping and instrumen- tions. Critical process parameters,
- Between raw materials or prod- tation, which contact a product or its such as temperature, pH, conduc-
ucts at various stages of quality components at a stage in the process tivity, bioburden, endotoxin, prod-
control or process step where such contact could influence the uct concentration, by-product lev-
- Between components or equip- quality, safety, purity, strength, or iden- els, purity, and stability are gener-
ment at different stages of clean- tity of the ultimate product. The pri- ally similar from process to process.
liness mary audience for this Chapter is pro- However, the acceptance criteria,
Segregation can be accomplished by cess and equipment engineers. implications, and applicable design
procedure, by spatial separation In general, biopharmaceutical pro- options from process to process may
(physical), by time (temporal), by cesses are similar in that nearly all vary significantly.
environmental control, or by pro- have fermentation/cell culture produc- General considerations for
cess design (system closure). tion steps, harvest steps, purification equipment design design con-
In a Multi-Product Operation, steps, formulation steps, and final bulk siderations common to most
products can be either campaigned filling steps. Although manufacturing biopharmaceutical unit operations.
or processed concurrently. For cam- processes may differ, certain Critical General equipment consider-
paigned products, the focus is on Process Parameters are consistent from ations, such as materials of con-
cleaning validation, changeover pro- product to product, and certain key struction, cleanability, avoiding
cedures between products, and line considerations for each processing step cross contamination, open vs. closed,
clearance procedures. For concur- apply to all processes. process monitoring, safety, contain-
rent product manufacture, the fo- Within each process step, there are ment, and maintenance, can be ap-
cus is on segregation, procedural process considerations driven by the plied to most process equipment,
controls, and avoidance of cross-con- overall philosophy of the organization and design considerations are out-
tamination. In all cases, the overall operating the process. The design ap- lined. Similarly, there are design
guiding principle is to ensure the proach that is chosen based on these considerations applying specifically
quality and safety of the product. considerations (GMP and business driv- to general particular areas such as
Manufacturing at Different ers) will result in a set of criteria to be cell culture and purification. These
Stages of Product Development used for both equipment selection and are outlined as well in the form of
is important for many biophar- overall facility design. There is no single checklists for the process and equip-
maceutical companies, particularly answer to the majority of the process ment engineer.
those facing their first major capital considerations mentioned. However, Specific equipment design con-
investment in manufacturing facili- the combinations of the choices and siderations design considerations
ties. While the regulations are clear solutions will define reasonable, com- that are unique to certain specific
in stating that GMP compliance is pliant process designs. biopharmaceutical process equip-
required for all stages of clinical Various types of equipment share ment types.
development, it is also recognized similar design considerations and re- Although a detailed analysis of
that in most cases the manufactur- quirements. Specifically, cleanability/ every unit operation used in biophar-
ing process is not completely de- drainability, surface finish, materials maceutical processes cannot be cov-
fined during early-stage clinical of construction, shear generation, clo- ered in this Guide, unit operations
work. It is important that process sure level, containment level, and pres- generally fall within these broad
issues having significant impact on sure/temperature requirements must process operation areas:
the facility design be locked down as be considered for virtually any piece of - Raw Material Storage/Handling
early as possible. The emphasis of equipment or device used in biological - Weigh/Dispense
process/facility design and valida- manufacturing. Improper consider- - Media/Buffer/Component Prepa-
tion during early-stage clinical ation can lead to processing systems ration/Hold
manufacturing should be placed on that are either not operable (placing - Inoculum Preparation
areas that have the greatest impact product at risk) or are operationally - Fermentation/Cell Culture
on product quality and consistency. inefficient (lower process yields). - Recovery/Harvest
Key topics addressed in this Chap- - Purification
4. Process and Equipment ter are: - Bulk Filling
The Chapter on Process and Equip- Simplified process flow diagrams of - CIP
ment is primarily concerned with de- several typical biopharma- - SIP
sign aspects of biopharmaceutical pro- ceutical processes. - Biowaste Deactivation
cesses and equipment, as opposed to the Critical process parameters that Specific design issues affecting unit
related operational aspects addressed are consistent from product to prod- operations in these areas are outlined.
in Chapter 3. More specifically, this uct. Key processing (critical) param-
Chapter deals with the design of eters for various processing steps

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5. Process Methods to define commissioning tails of the biological process to be
Support and Utilities and qualification requirements for controlled. What are the critical oper-
This Chapter provides guidance in de- process support utilities ating conditions? What can adversely
sign and operation of utility services A summary of key concepts for affect the process or product? Once the
supporting the manufacturing of biopharmaceutical water systems process and critical operating param-
biopharmaceutical products. Utility is provided eters are identified, the optimal level
systems addressed in the Chapter in- of automation versus control via
clude: 6. Facility manual procedures may be determined.
Pharmaceutical Water Systems Biopharmaceutical manufacturing fa- Automation is not a GMP require-
Cleaning, Sterilization, and Depyro- cilities are very complex and result ment. However, when automation is
genation Systems from projects that focus on the at- used, it carries with it GMP require-
Process and Utility Gases tributes of the product(s) being pro- ments. If properly applied and vali-
Process Temperature Control Sys- duced, the attributes of the process, dated, automation can help achieve
tems and the facility attributes needed to ongoing GMP compliance. When not
Biowaste and Process Waste Han- meet cGMP guidelines. The facility properly managed and designed, auto-
dling design team should become familiar mation can result in problems with
Seal Support Systems with the topics discussed in the Chap- project schedule and cost.
Plumbing and Piping Systems ter to understand how each will affect Topics covered in this Chapter are
Emergency Power the final facility design and operation. organized as follows:
The Chapter focuses on process sup- This Chapter will review: Biopharmaceutical Automation Is-
port systems that affect ability to meet The impacts of process and unit sues
GMP production requirements. The operations on facility design Level of Automation
Chapter identifies the major GMP is- How product attributes play a key Biopharmaceutical Unit Operations
sues for each of the systems addressed. role in facility definition - Fermentation/Cell Culture
Guidance is provided in design of sys- The importance of adjacencies in - Cross Flow Filtration
tems to minimize risks of product con- defining operational flow to mini- - Chromatography
tamination or unreliable production. mize potential contamination op- - SIP
For purposes of qualification and portunities - CIP
commissioning, the Chapter categorizes The impacts of containment and Control System Maintenance
process support utilities as having Di- closed processing on facility design Validation of Automation Systems
rect Impact, Indirect Impact, and No The definition of area environments
Impact on product. The Chapter rec- and their impact on facility layout 8. Commissioning
ommends full qualification and com- and design and Qualification
missioning of Direct Impact systems. The issues related to single product A biopharmaceutical manufacturing fa-
Systems with Indirect Impact or No vs. multi product production phi- cility is commissioned and qualified in
Impact should be commissioned consis- losophy the same manner as any other pharma-
tent with Good Engineering Practice. Air lock and gowning room alterna- ceutical manufacturing facility. Many
tives aspects of the qualification of aseptic
Key Concepts Considerations for effective process manufacturing facilities apply to classi-
discussed in this Chapter and production support areas fied spaces in biopharmaceutical facili-
Process support system features that Regulatory considerations in facil- ties, yet there are many areas that re-
affect GMP are identified, and vul- ity design quire only commissioning in accordance
nerable characteristics are ex- Layout alternatives, when is verti- with Good Engineering Practice.
plained cal flow practical It is imperative that, before detail
Methods to minimize product con- Finishes are covered in other design begins, the owner and engi-
tamination risks from process sup- Baseline Guides, and are refer- neers develop User Requirements
port utility systems are presented enced in this Chapter (What the facility is to do) and a Func-
Except when required for safety or Discretionary (non-GMP) consider- tional Design (How the facility will
operational reasons, system design ations work and protect the product). These
should minimize the need to service activities will identify product/process
and otherwise access process sup- 7. Process Controls critical parameters and their accep-
port systems from within produc- This Chapter on Process Controls and tance criteria (forward processing cri-
tion areas Automation provides points to consider teria), against which post-construction
Systems that might enable trans- when developing instrumentation and qualification will verify performance
mission of contaminants are identi- automation strategies for of the direct impact systems that are
fied with methods for prevention Biopharmaceutical operations. This identified in Functional Design.
provided process starts by determining the de-

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The ISPE Baseline Guide for Com-
missioning and Qualification provides
valuable guidance in identifying the
systems needing qualification. Rather
than restating the entire Guide, a few
highlights are provided in this Chap-
ter. The facility engineer is directed to
the ISPE Baseline Guide for Commis-
sioning and Qualification for further
information.

9. Glossary
A glossary of pharmaceutical industry
terminology relevant to the ISPE
Baseline Guide for Biopharma-
ceuticals.

10. Appendix -
European Aspects
The purpose of this appendix is to high-
light the general requirements in Eu-
rope and to point out the differences
between Europe and the US. Within
Europe, the majority of countries are
covered by the European Union (EU).
There are countries in Europe outside
EU, such as Switzerland, that are cov-
ered by their own national regulations.
The general trend is to harmonize the
regulatory requirements worldwide,
but differences still exist. Organiza-
tions like ICH are the main drivers for
that development.
Within Europe, the EU directives
are harmonizing general requirements,
giving the minimum standards. The
national laws need to comply with
these, but are allowed to be more strin-
gent.

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