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Master planning and validation. Part 2: System definition
Article in BioPharm · April 2000
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James Agalloco
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Master Planning & Validation
James Agalloco
Agalloco & Associates
Acknowledgment
The author is deeply indebted to Mr. Phil DeSantis of Fluor Daniel, who could easily be listed as
a second author on this entire effort. The many discussions Phil and I have had over the past 15
years on the subject of validation in general, and more narrowly the management of it have formed
the basis for much of what is included in this effort. In many ways this effort is as much Phil’s as
it is my own. Phil was also assisted this author by reviewing the early drafts prior to submission.
Introduction
Master planning is an activity which utilizes project management tools to assist in the
development and execution of a validation project activity. It incorporates elements of project
definition, coordination, administration, scheduling and budgeting to assist the validation project
team in fulfilling the validation requirements. Some in the industry have gone so far as to
suggest it is a CGMP requirement for capital projects executed in the healthcare industry. To
this writer that view seems a bit extreme, master plans while extremely useful are not required
by any existing regulation, nor should they be. There existence is not a guarantee of success,
nor is their absence a predictor of failure. There are many instances where the absence of a
sound master plan has been detrimental to the project, and perhaps an equal number where the
plan provided no meaningful advantage to the firm. The master plan should be considered as a
management tool, to be used like every other tool, for the appropriate task at the appropriate
time. This effort will address various aspects of master planning, with the hope that the insights
provided will be of some benefit to the reader in the use of this tool.
Terminology
Master planning, could also be termed validation master planning, validation project planning or
validation planning. The specific name for it is largely irrelevant [though there are some who
would argue that a master plan includes lesser documents termed, project or task plans]. What
is essential to remember that it is a means to organize the various activities which culminate in
the validation of a specific project, product or system. Recognizing that validation projects can
substantially vary in scope and complexity should suggest that master plans will vary similarly.
The best plan is one that is tailored to the project specific management requirements of the
project, and while there are some common templates in use, it would impossible for a generic
plan or template to meet the needs of every possible project. For this reason, some
practitioners have chosen to define their planing tools more narrowly, with a single master
validation plan, supported by project plans. This type of formality may be beneficial to some,
but it is largely a decision made by a specific firm or firms, and should not be considered a
universal practice. What is important is not what the tool is called, but rather how it is applied,
i.e., to loosen a bolt, a wrench is often used, but specifying the type of wrench does not change
the task required.
Master Planning Adages
The nice thing about not planning is that failure comes as a surprise.
If you don’t know where you are going, you’re likely to end up someplace else
Prior planning prevents p--- poor performance
Plan Ahead
Why Develop a Validation Master Plan?
The answer to this has already been already given in the introduction - master planning is an
activity which utilizes project management tools to assist in the development and execution of a
validation activity. Within this overall definition, there are numerous advantages that a plan can
provide both during the validation project execution and later during the operation of the facility,
system, process or equipment. Some of these are outlined below:
Structures Validation Activities - The various tasks necessary for the validation are
assembled in a logical manner to facilitate the identification of project milestones, critical
path, identification of resources, etc. An unordered pile of validation protocols provides
some of the same information, but without ensuring that related activities are considered
in proper sequence, e.g., feed water must be available to feed the clean steam, clean
steam must be available to supply the autoclave, the autoclave must be validated to
sterilize the parts, the parts must be sterile to perform the media fill. Other protocols
might fit together in a parallel arrangement, e.g., stopper sterilization, container heat
depyrogenation and product filtration sterilization are all required before filling sterile
products. The master planning effort can help ensure that the various tasks associated
are identified, organized and executed in a manner that minimizes the project time line,
while maximizing resource [materials, equipment, personnel and funds] utilization.
Project Familiarization - In any sizable validation project, there will be individuals who will
need to gain reasonable familiarity with the project within a brief period of time. A sound
master plan can enable individuals to gain that knowledge quickly. It can be used with
both internal and external personnel who join the effort partway through its completion,
or even with individuals whose duties are only peripherally affected but who require
some overall project knowledge. Individuals hired after the completion of the project can
gain rapid insight into the project and facility in the descriptive parts of the plan.
Management Introduction - Senior management of the firm can use the plan to
understand the scope of the validation effort, and to gauge the progress made towards
completion against it. The plan provides sufficient overview information to ease their
education in the nuances of the project. Where the plan includes budgetary and
schedule information [just as included in capital project plans], senior management will
have a greater awareness of the business aspects of the validation effort.
Regulatory Interaction - The type of project familiarization possible through the
availability of a plan can be used to advantage with regulators. The plan can convey to
the inspector the scope of the effort, and ease their concerns regarding possible
oversight on the part of the firm. Pieces of the plan can be used in initial regulatory
discussions with regulators to assess their acceptance of the firm’s intended validation
approach. This is of particular benefit, where the firm’s validation proposed validation
approach is novel or potentially controversial, by opening a dialogue early in the project.
Convertible into Drug Master File / New Drug Application - The descriptive parts of a
validation master plan are quite to the type of information provided in a DMF or CMC
section of an NDA. The effort expended in a facility master plan can often be reused
with only minimal reformatting in these other regulatory documents.
Useful with 3rd Parties - Validation master plans have been used in the solicitation of
bids for validation project execution. As the plan delineates the full scope of the
validation effort, validation services contractors can use it to provide bids to the project
owner for the execution of some or all of the tasks. It can also be used in discussions
with firms who are considering using the facility as a contract manufacturing site.
Validation Program Foundation - Where a firm is building its first CGMP facility, the
validation master plan can serve as the initial foundation for the organization’s validation
program, both for this project and others to follow. It can define templates, methods, and
procedures which will guide the firm in later projects. Since the construction of a CGMP
facility may represent the first time a firm may have to execute a large number of
validation activities, it can provide the framework for all subsequent validation efforts the
company might undertake.
Resource Planning & Scheduling - Project planning in the form of Gant or Critical Path
Analysis charts are often developed in conjunction with a capital project master plan.
These can be used in the management of the validation activities, and assist the firm in
allocation of resources. These tools can be used both during the initial planning of the
validation effort and later on during the execution of the protocols.
Protocol / Report Outlines - Master plan normally include substantial information on the
validation requirements which must be satisfied. The plan can also define such aspects
as format, structure, approvals, etc. for the validation project for those firms which have
not yet established their validation program. This is also necessary useful when working
with outside contractors.
Eases Protocol Preparation - The master plan can provide specific details which can be
inserted into the validation protocols. By providing details requirements at early stages
of the project, the design of the facility and systems can be modified to ensure that the
validation expectations can be readily fulfilled. The extent to which the master plan
provides definitive criteria for the various validation to be performed, will determine its
utility for this purpose. If the plan is heavily detailed, the protocol preparation will be
eased. In the absence of clear requirements in the plan, the protocol preparation effort
will of necessity have to be more extensive. The development of a detailed master plan
early in the project can be used to shift a portion of the validation workload to this earlier
period in the project when the validation resources are more available.
Procedure Definition - A common element of many plans is the identification of the
operating procedures necessary to operate the facility or system once validated. This is
especially important for new company’s where the majority of these procedures must be
developed for the first time. In some instances, certain key procedures such as
calibration, training, etc., are included in the master plan. Identification of SOPs at this
early stage alerts management to the need for resources to develop them in a timely
manner.
What Types of Plans are Possible?
Validation plans can encompass a variety of project scopes, ranging from a plan drawn to assist
an entire corporation with multiple products and facilities, to those focusing on a single project of
a far smaller scale.
Corporate - This type of plan would encompass the overall program for a corporation,
which for a large organization might include multiple products at multiple sites. For a
smaller company, this type of plan might be comparable to what a larger firm might
implement for a single site. By its very nature, this type of plan tends to be more general
in nature and might be more of a validation policy statement than an actual validation
plan.
Site - This plan addresses the activities performed at a single location, and could
certainly vary with the size of the site. The large multi-national companies often have
sites with multiple production and developmental activities. Thus a plan for a single site
of this type might be substantially more complex than a corporate plan for a smaller firm.
Project / Facility - A plan developed for a single project or facility is perhaps most
common. This would define the validation requirements for a single production or
developmental facility. The larger companies in our industry frequently make
investments in new facilities to support the production of a major new product. Rather
than incorporate these operations into existing operating areas, the advantage of a new
facility is the ability to tailor the design to meet the specific requirements of the new
product. This type of investment is also likely when a firm first establishes a commercial
scale facility for its products, as might be the case with a biotechnology firm awaiting
approval of their first product. R&D areas and pilot plants will have their validation
programs established in a plan of this type.
Product - A product based plan might be very similar to that developed for a project or
facility, with the primary difference that this type of plan would focus on the validation
efforts supporting a single product, which might be produced in a series of steps and
processes encompassing multiple facilities, multiple sites, or even multiple corporations.
Activity - A plan written for an activity would be one established to structure the
validation of a particular type. An activity focused validation plan could be written for
cleaning, terminal sterilization or analytical methods.
How Large Should a Master Plan Be?
It might appear from reviewing the various types listed above that plans could vary from a
relatively brief document addressing a single product or activity, to a far more extensive
document covering the programs at a large multi-national organization. That however is not the
case, master validation plans should be essentially the same size with varying levels of detail.
A plan for a multi-national would of necessity be fairly general in nature, and as mentioned
previously might be more of a validation policy or position statement, covering the subject in a
fairly general fashion. At the other end of the spectrum, a plan targeted to a single product or
activity would be far more detailed, and might summarize many of the key criteria to be met in
the validation effort. In the author’s experience the most effective plans are approximately 50 to
75 pages long, including the same types of information with varying amounts of detail
depending the goals of the plan. Phil DeSantis likes to recommend that a plan be readable in a
single sitting, suggesting that it require no more than 1 to 1½ hours to read in its entirety.
Having seen master plans which extend to multiple volumes covering hundreds of pages, which
are nothing more than a compilation of protocols, I certainly concur that it is better to err on the
side of brevity than to drone on endlessly attempting to provide every nuance of detail. A
extremely large plan is difficult to be use effectively and much more difficult to maintain current.
It is certainly acceptable to take a larger project and divide the validation plan into several
subsections. The overall validation plan might be for the facility proper, and it would introduce
the subordinate plans which could address such aspects as control systems or cleaning
validation. The subordinate plans would address only a single subject and could presumably be
somewhat more compact as a result.
NOTE: In the rest of the document, the assumption is made that the type of plan being
considered is for a project, facility or product as this is perhaps the most common
application of master planning and illustrates the concepts and practices best.
When is a Master Plan Not Required?
First it must be recognized that there are no regulations which mandate that a firm have a
validation plan. Despite what one may here at conferences or papers, master plans are not a
CGMP requirement. The more complex the project the more a plan can be valuable in
providing some degree of structure to the effort. A very simple project could certainly be
completed successfully without a plan. As the individual responsible for organizing the
validation of one of the first heavily automated parenteral facilities in the mid-1980's, no
validation master plan was developed, at least not in the formal sense. Over the course of the
project we developed a number of documents and used a variety of management tools to
organize our work, but there was nothing prepared which resembled a validation master plan.
Our effort was ultimately successful, for what was and still is one of the larger facilities of its
kind. Clearly it is possible to complete a complex validation project without a plan. Despite
what I’ve just written, I would certainly agree that if I were to undertake a similar scale project
today, or even a much smaller project, I would prefer to develop a validation master plan for that
effort.
There is a point at which the need for a plan can certainly be questioned. In several
recent projects I have been required by my client to prepare a master plan for the project. In
one case, the total number of protocols which had to be developed for the project was only 6
encompassing both I/OQ and PQ activities. It appeared to me that the scope of the project did
not warrant the development of a master plan, as there appeared to be very little chance of the
project overwhelming anyone’s ability to comprehend what was intended or how it was to be
executed. Nevertheless, this firm had a corporate policy which mandated that for validation
projects in which an outside firm was utilized that a master planning document be prepared. I
conceded the point and wrote the plan. It was the briefest I have ever prepared, a mere 17
pages, and I should also note was something which I never referred to during the entire project
execution. I did not ask the firm if they would have prepared a plan had they performed the
project with internal resources, I fear that they might have.
A parallel I might draw is the preparation of a shopping list before visiting the market. If
I’m only going for few items, I will trust my memory and not prepare one before I shop. As the
number of items I require increases, the more likely I am to prepare a list, and actually use it
during the course of my shopping. A validation master plan can be looked at similarly, for
simple project the effort expended in preparing, reviewing and approving a master plan may
have no justifiable return. At what point this occurs for a project will depend upon the
capabilities of the firm and the experience of their staff.
When Should a Master Plan be Written?
Unlike the preceding question, there is most certainly a preferred point in a project at which the
preparation of a validation plan is most advantageous. This occurs after the firm has
established some clear objectives for its project. It must be able to answer some simple
questions as to the scope, size and goals of the project. This generally happens when a firm
has completed its preliminary design process. The original wish list of project goals will have
been weaned down to some agreed upon features which the project must include. This is the
optimum time for plan development, the narrowing of project options that has occurred in
preliminary design, allows the plan to be written with a firm sense of what the project objectives
are. If it is prepared before this point, there are likely to be a series of drafts reflecting the
changing nature of the project. It is preferable to wait until agreement has been reached on the
scope of the project, to prevent this. If the plan is prepared concurrent with the start of detailed
design for the project, the master plan can be used to help finalize that design, while the
availability of some design information makes the preparation of a meaningful plan possible.
Developed early enough the validation plan can alert the design team to the need for sample
points in the water systems, access points for thermocouples into pressure vessels for SIP, and
similar items. If the plan is developed after the completion of detailed design, the opportunity to
identify these types of items may be lost, but provided the plan is available prior to the start of
the validation effort it can still prove extremely useful.
I have heard instances where a firm has prepare a “validation master plan”
retrospectively. That is after the facility was completed, but prior to regulatory inspection. While
hardly a planning document in the sense that it was prepared after the activities were
completed, it still enabled the firm to realize some of the benefits of a plan prepared in the more
conventional or prospective manner. The firm was able to use the “plan” as part of their
regulatory interaction to good advantage. While it missed the ability to use the plan in
managing their validation effort, they were still able to use it effectively to manage their
regulatory interaction. Of course the advantages related to having the plan for a completed
facility were also possible
Who Should Write the Plan?
Validation plans are best written by a single individual who possesses a knowledge of the
project and is sufficiently well versed in the validation requirements for the project. A single
author should be able to structure the document with a consistent level of detail, with minimal
redundancy far easier than a team. This person could be an employee of the firm, a consultant,
or an employee of a engineering / architectural firm. Regardless who is the author, it is
essential that the plan extend into the performance qualification of the product / processes for
which the project is intended. This aspect of the validation is the part which draws the most
attention from regulators, and is sometimes the most neglected piece. Whomever prepares the
plan must be conversant enough in validation of these production processes to insure that these
are addressed in sufficient detail..
What Information is Needed to Prepare a Master Plan?
Before preparing a master plan, the following information should be assembled. The higher the
accuracy of this information, the easier the task of actually writing the plan will be.
Facility Layout - A layout of the facility helps define the relationship between the various
operating, support and other areas of the facility. The layout helps support the suitability
of material, component, personnel and equipment flows. Depending upon the usage of
the facility, the layout can have a profound impact on the suitability of the facility for its
intended purpose. The layout is not a construction drawing and may be more of a
sketch than a final document.
Process Description - An important element of any production facility is a description of
the process(es) to be performed within it. This could include: fermentation, and
purification for a biotechnology product; the unit operations possible in a multi-product
dosage form facility, or the chemical reactions which are utilized in an bulk
pharmaceutical plant. For a single product plant, this description should be detailed
enough to provide a complete understanding of the process involved in it’s manufacture.
For larger scale facilities, the description should become more of an outline of
production capabilities rather than the specifics of any individual process. For
developmental facilities, the capabilities of the facility are summarized to establish the
flexible nature of the use to which the facility will be put. A visual presentation of this
information can prove useful in multi-step processes.
Product Description - Details of the product(s) to be manufactured within the facility are
also included. Again the level of detail will vary with the number of products being
produced. This section would be omitted in a developmental facility where the
production of any individual product or product type is more incidental than mandatory.
Equipment List - The focus of the qualification / validation effort is often the equipment
which is installed within the facility. This list can be further subdivided by process or
location within the facility if necessary. Specifics of manufacturer, model, capacity, etc. if
known can also be beneficial. This list is usually the result of having finalized the
process / product for which the facility is to be utilized. Equipment which is always
operated as an assembly, e.g., a packaging line, is more commonly identified as a single
entry rather than being broken down into its component parts.
Utility List - For larger facilities, where the number of utility systems is large, then a
separate list of utilities to be provided can be beneficial. Once the process equipment
has been identified, the development of the utilities needed to support them can be
developed. In smaller facilities, this list is better integrated with the equipment list. As
suggested with the process equipment, it is preferable to identify each utility system,
e.g., the water for injection system including pretreatment, still, storage tank and
distribution system than to address the equipment individually.
Controlled Environment Requirements - Facilities which have classified and/or controlled
environments should have these identified in the plan as well. These should be
identified on the facility layout. The elements of the HVAC or other systems which
support these environments should be known as well.
Process Control - Where the facility is to be supported by a control system, as might be
found in a BPC or biotech facility to support the key production processes, then some
elements of the any proposed control system design would be provided. This section
should be omitted where an overall control system is not present. Aspects of computer
controlled equipment would then be included within the equipment / utility descriptions
proper.
Project Schedule - Planning the execution of a validation effort must consider the overall
schedule for the product. A project which is design-build will require a different
validation timetable, than one which follows a more typical design-bid-contract-build
procedure.
The quality of the plan which is developed is dependent upon the accuracy of the information
provided to the author. This oftentimes implies a trade off, writing a plan early in the design
phase allows more time for plan development, but will likely mean that less specific information
will be available to the author. Deferring the plan development, allows for more detailed
information to be communicated to the author but minimizes the opportunity to integrate
validation concerns into the design. The earlier discussion on the timing of plan development
should also be considered in this same context.
What is Included in a Master Plan?
The following are typical sections of a master plan. The order of presentation is flexible as there
are no standards which mandate any specific order.
Introduction - Introduction to the project scope, location, and timing. Includes
responsibilities for protocol, SOP, report and other documentation preparation and
approval. Identifies who is responsible for the various activities. A general validation
SOP or policy statement is frequently included.
Facility/Process/Product Description - A concise but complete description of the entire
project is provided. It will provide information on: materials of construction; layout and
flow of personnel, materials, and components; description of utility and support systems;
brief description of the processes to be performed and products to be made in the
facility. Major equipment is described with minimal details. It generally includes
drawings of the facility and process flow diagrams. Information on the product(s) to be
manufactured is also provided. This section can be divided into 3 parts for larger scale
projects.
Automation / Process Control Considerations - Computerized information, laboratory and
process control systems are described in sufficient detail to delineate the validation
requirements. This section may be omitted if the level of automation is minimal. This
information can also be included in the equipment section where automation is limited to
equipment control.
List of Systems / Processes / Products to be Qualified / Validated - This section is
sometimes referred to as system definition. Equipment, systems and products are listed
in a matrix format which describes the extent of validation required [i.e. IQ, OQ, or PQ]
as part of the project. Additional breakout of computerized, cleaning and sterilization
validation requirements can be added if the project is complex enough.
Protocol Outlines / Acceptance Criteria - The overall protocol requirements and
acceptance criteria [general and specific] for the items listed in the prior section are
provided. Emphasis should be on quantitative criteria throughout.
Project Specific Issues - This section is included where there are elements of the
validation effort which bear greater clarification or emphasis. Subjects which the author
has addressed in this manner include: computerized systems, cleaning, isolation
technology, and lyophilization.
Document Formats - The format to be used for protocols, reports and procedures is
described. This is particularly useful for companies embarking on their first CGMP
facility and for any project in which multiple organizations will be executing a portion of
the overall validation effort.
Standard Operating Procedures - List of SOP's [new or existing] necessary to operate
the facility. The inclusion of this list serves to highlight the number of procedures
required to operate and maintain the facility.
Planning & Schedules - An estimate of the staffing requirements to complete the
validation effort described in the plan. A preliminary schedule of required activities is
prepared to help estimate appropriate manning levels.
Plan Introduction
This section of the plan serves to explain the intentions of the project. It describes the what,
when, where, why, who and how of the project. This section is typically less than a page and
broadly defines the scope of the project. This section should provide a brief summary of all of
the following sections.
Descriptions
The descriptive part of the plan can include all three elements: facility , process and product. In
developmental projects, the absence of a defined product or process precludes any real details
in these areas. In those instances, the description of process and product should speak to the
capabilities of the facility, in terms such as: non-sterile coated and uncoated tablets and
capsules in batch sizes up to 50 kg. In commercial plants, the product and process sections
should be far more complete. In the author’s experience this is one area which is frequently
inadequate in many plans. There is a tendency on the part of some plan preparers to think of
the validation as it relates only to the equipment and systems, and give only minimal, if any
attention to the processes and products which those equipment and utility systems are
expected to produce. This leads the firm through fairly straightforward execution of their
installation and operational qualification, but with little insight into how the always critical
performance qualification activities which follow are to be executed.
Facility Description - Facility descriptions are usually included in master plans, though
plans written for aspects such as cleaning and analytical methods might omit this
information. Included in this section would be a sketch or single line drawing showing
the overall facility layout with major equipment and classified environments indicated
directly on it. This diagram is not a mechanical drawing, the additional information
provided on a construction drawing is not necessary for the purposes of master
planning, and even tends to confuse the description somewhat. The diagram can be
supplemented with a series of overlays which depict personnel / material / component
and equipment flows through the facility. A listing of classified and controlled
environments can be included where provided. This can be augmented with diagram(s)
depicting and environmentally controlled or limited access zones or areas. For facilities
where microbial control is critical, information on the materials of construction should be
included. The emphasis in this section should be visual rather than written, the
information is often best conveyed in simple diagrams or sketches.
Process Description - The process description should explain in words the processes to
be performed within the facility. This should identify major process steps in their proper
sequence. For a tablet process, these might be identified as weighing, blending,
granulation, milling, final blending and compressing. A biotech process might be
described as cell bank harvest, cell propagation, fermentation, cell lysis, extraction,
ultrafiltration, chromatography and bulk packaging. In a BPC facility, the various steps of
reaction chemistry would be described. The process description can be presented in
various formats: written narratives, annotated block diagrams, or process flow diagrams.
The inclusion of critical parameters (if known) serves to increase the utility of the
descriptive information. Where multiple products are manufactured, the process for
each can be provided. In parenteral and biotech facilities, where control of
microorganism of a major importance, descriptions of the major utility systems,
especially Water for Injection, and the primary sterilization equipment; steam sterilizers,
dry heat tunnels and ovens, etc. is commonplace.
Product Description - An portion of the master planning effort which is often under
represented is the product description. It should include information on product type(s),
production volume [optional], batch size(s), formulation [optional], and important product
features (color, viscosity, flavor, etc.) [optional], package(s). Other aspects to include
are product solubility, operator safety and handling aspects, and stability (in the
presence of heat, moisture, light, and air). These last elements may have an impact on
the validation program: solubility of the materials impacts the cleaning validation effort;
safety and handling concerns may mandate facility changes to protect the workers and
the environment; while stability (in-process and/or finished goods) will dictate specialized
requirements to mitigate potential degradation of the materials.
Other Descriptions - Detailed descriptions of other types are certainly possible. In past
plans the author has included sections on cleaning procedures, control systems and
isolation technology. The need for such descriptions is dependent upon the specific
elements of the particular project which requires additional attention.
Systems Definition
This is the core of the plan, in which the scope of the validation effort can be rapidly understood.
The centerpiece of this section is often a table which lists the systems, equipment, processes
and products and then identifies whether they are subject to commissioning, qualification
and/or validation. In this author’s opinion, too many master plans do a incomplete job in this
area, they restrict the list to physical items of equipment, or facility elements, and omit such
critical aspects as sanitization, cleaning, production processes and products. This is
unfortunate, as the true intent of the validation master plan is to support the start of production
of a product, not to document a construction effort. Regulators and owners should only be
concerned with equipment and facilities aspects to the extent that they can impact the identity,
quality, purity and efficacy of the materials being produced. Plans which address only the
equipment and facilities elements are perhaps more accurately termed “qualification master
plans”. Only when they include supportive guidance on the processes and production methods
for the product(s) being manufactured can they be considered true “validation master plans”.
Where these aspects are minimized, or worse yet ignored, the utility of the master plan is
severely diminished.
Additional utility for this effort can be obtained through an expansion in the categories beyond
merely commissioning, qualification and validation. By adding to the number of columns such
aspects as cleaning, sterilization, control systems, the full scope of the effort can be more
readily understood. The following table is an example of a listing which includes enhancements
over those typically found.
Equipment, Systems and Procedures to be Validated
East Antartica, Sterile Products Facility
Description Commiss
ioning
I/OQ PQ Sterilize Clean Control
System
Fixed Manufacturing Tank X X X
Fixed Holding Tank X X X X
Portable Tanks X X X
Homogenizer X X X X X
CIP System X X
Vial Washer X X X
Depyrogenation Tunnel X X X
Accumulation Table X
Vial Filler/Stoppering X X X X X
Vial Capper X X X X
Vial Inspection X
Labeler/Label Verification X X X
Bail Bander X
Vial Accumulator X
Tray Maker X
Overwrapper X
Palletizer X
Case Packer X
Stopper Processor X X X X
Steam Sterilizer X X X
Parts Cabinet Washer X X
Ultrasonic Parts Washer X X X
Autoclave Bag Sealers X X
Calibration Equipment X
Filter Integrity Apparatus X X
HEPA Vacuum Cleaners X
Clean Steam System X X X
WFI System X X X
Deionized Water System X X
HVAC System #1 - Aseptic Core X X X
HVAC System #2 - Preparations
Area
X X X
Laminar Air Flow Hoods X X
HVAC System #3 - Unclassed
areas
X
Automated Air Locks X X
Fixed Environmental Monitoring
System
X X
Portable Environmental Monitoring
Units
X
Building Monitoring System X X X
Compressed Air System X X X
Plant Steam X
City Water System X
Sanitary Drainage System X
Process Drainage System X
Condensate Return System X
Product 1 Solution X X
Product 2 Solution X X
Product 3 Suspension X X
Gowning Procedures X
Manual Inspection of Vials X
Media Fills X
Manual Cleaning X X
Sanitization X
As this table represents the centerpiece of the plan, some clarification of its design and use is
necessary to fully understand it and the plan which is built around it.
1. Note how equipment items for which cleaning validation must be performed are
identified in a column designated for that purpose. Similarly, the inclusion of the
products and such activities as vial inspection, and media fills serves as a reminder that
their validation must also be considered in the project scope. The homogenizer is the
subject of several different PQ efforts. Its sterilization, cleaning, control system and
performance in properly sizing the drug particles must all be validated. Considering that
each of these activities may be defined in a separate protocol, the inclusion of the
additional columns helps clarify the validation requirements more clearly than had they
been lumped together.
2. Note also that there are systems and equipment indicated in the list which are not
subject to formal installation / operational qualification. These items are commissioned,
an exercise substantially less formal than qualification which serves merely to confirm
that the system or equipment has been installed properly or meets its very limited
operational criteria. Commissioning is generally done without formally approved
protocols and is appropriate for elements of the facility which have minimal impact on
key product quality attributes.
3. The inclusion of systems in the table comprised of many different small equipment items
might suggest that an overall I/OQ be prepared. That is certainly a option for a small
system, but it is preferable to prepare individual I/OQ documents for the individual items.
Thus at the I/OQ stage a water system would system would have separate I/OQ’s for
each piece of equipment in the pretreatment system, i.e.; sand filter, carbon filter,
deionization beds, ultra filter, etc., During the PQ of this system, it would be perhaps
easier to prepare a single protocol addressing the sampling throughout the pretreatment,
storage and distribution systems. The table merely serves to indicate what level of
documentation the system will be subjected to rather than define exactly how that
documentation is to be assembled.
4. A number of the required PQ activities are those which support the standard operating
procedures for the various equipment, systems and other activities. Draft SOP’s are
validated in the PQ phases of the project. The approval of the PQ reports should be
accomplished in conjunction with the approval of the SOP for the process which the PQ
validates. After all, for the SOP to be approved, its requirements and conditions must be
supported by validation data which confirms the acceptability of the procedure details.
5. The table above listed installation and operational qualification together as a single
activity. Considering that in the vast majority of efforts, a system which is subject to
installation qualification will also be subject to operational qualification, their identification
as a common requirement is straightforward. The author’s preference is to more closely
integrate them as a single activity entitled qualification, with a single protocol and a
single report. Given the absence of regulatory guidance in this area, the combination of
these activities is certainly acceptable.
6. The table also included a number of activities; sanitization, media fills, manual cleaning,
etc. which had only a PQ stage. Their inclusion identifies that their completion is
required to have a validated facility, despite the absence of a individual I/OQ activity
preceding it. Each of these items should have its validation requirements defined in the
specific acceptance criteria section of the plan [see later section].
General Acceptance Criteria
To avoid unnecessary redundancy in master plans, a common practice is to include a section
entitled general acceptance criteria. These criteria are universal and applicable to all items in
the table which have that column checked. General acceptance criteria can be related to any or
all of the various stages: commissioning, installation, operational or performance qualification.
Depending upon the stage for which the criteria are established, these will be repeated in the
appropriate protocol for each system or piece of equipment. The following are examples of
typical general acceptance criteria for each stage.
Commissioning - typical commissioning requirements
All equipment, piping, wiring, instrumentation must be clearly identified in the field and
conform to the descriptions provided in the appropriate drawing or other documentation.
All piping systems shall have been cleaned to remove construction debris and such
cleaning shall be documented.
Installation Qualification - typical general acceptance criteria
Change control on all equipment and systems in the facility shall be instituted from the
start of the IQ for each item. Any changes made subsequent to the start of the IQ must
be made in accord with site equipment change control procedure.
For all automated systems, written or electronic [human readable] documentation of all
application software shall be available. Software shall be annotated to allow for
comparison to written process descriptions. A flow chart shall be supplied outlining each
application software program.
Operational Qualification - typical general acceptance criteria
Systems and equipment must function reliably under environmental conditions
approximating those of normal use.
Draft written Standard Operating Procedures shall have been prepared for the operation
of each system and piece of equipment. These procedures will be finalized and formally
approved after completion of the PQ evaluation of each system.
All instrumentation [indicating and recording] must be calibrated using written
procedures. Calibrations shall be traceable to the appropriate national or international
standards wherever possible.
Performance Qualification - typical general acceptance criteria
Critical operating parameters shall be independently measured and documented in each
trial. Such measurements will be made with traceable instruments where possible.
Systems shall perform as intended with regard to expected yields, volumes, flow rates,
as described in the appropriate SOP's.
Components, materials, and products processed by each system or piece of equipment
shall conform to appropriate in-process or finished goods specifications.
It should be recognized that some equipment and utility items in the system definition table will
only have general acceptance criteria, and will only be subject to the requirements of this
section. Other systems and pieces of equipment will be subject to both the general criteria, and
also to criteria specific for that system.
Specific Acceptance Criteria
Some of the equipment listed in the system definition section of the master plan will have criteria
which are unique to that system. These are defined individually for each system or equipment
item. In comparison to the general acceptance criteria which as noted above are rather
subjective or rule oriented, the specific criteria should be largely quantitative in nature. In this
author’s opinion, the best master plans are those which include numerical requirements
wherever possible. The reliance on rigorous criteria facilitates the subsequent preparation of
validation protocols as the more meaningful criteria for those protocols has been already
defined and embodied in the master plan. As setting acceptance limits is among the more
contentious aspects of protocol preparation, moving it to the master plan stage allows more time
for consensus building. The following examples are drawn from a plan the author prepared
some years back:
Depyrogenation Tunnel
Installation Qualification
1. The HEPA filters installed in the machine shall be certified to retain a
minimum of 99.97% of particles larger than 0.5 micrometer.
Operational Qualification
1. Air within the tunnel shall meet FS 209 E Class 100 requirements at
operating temperature [circa 330°C].
2. The tunnel shall be able to operate properly while maintaining a maximum
0.10" H2O pressure differential from discharge to infeed.
3. The dry heat tunnel shall operate properly throughout its operating range
of 0 to 100, 100 and 200 mL vials per minute.
4. The tunnel shall maintain a distribution temperature range [belt edge to
belt edge] of not more than 30°C throughout its length when empty.
5. The tunnel shall maintain a distribution temperature range [belt edge to
belt edge] of not more than 25°C throughout its length when full of 200
mL vials.
Performance Qualification
1. The tunnel shall be capable of a minimum 3.0 log reduction in endotoxin
content for all vial sizes. The minimum challenge level shall be 1,000
Eu/vial [recoverable].
2. There shall be no increase in vial particulate matter content as a result of
passage through the tunnel.
3. The tunnel shall maintain a penetration temperature range [belt edge to
belt edge] of not more than 20°C throughout its length when full of 200
mL vials.
The inclusion of quantitative criteria in the master plan is sometimes deemed an unnecessary
exercise by some individuals. Their position is that such details belong in the validation
protocols. In the author’s opinion, this reduces the value of the plan substantially. If one only
wanted to know what was going to be commissioned, qualified or validated, the plan could
consist only of the system definition table described earlier. It is only when the detailed
requirements are included that a real feel for the scope of the effort can be obtained. A plan
without numbers is like a chocolate chip cookie without the chocolate chips, it has the name but
none of the substance which makes it what is should be.
The numerical values used in this section of the plan can be drawn from a number of sources:
regulatory or pharmacopieal guidance, industry guidelines, equipment specifications, vendor
recommendations, design documentation, or even experience in prior or similar installations. e
In preparing the specific acceptance criteria section, there will be times when there are no
commonly agreed upon numerical criteria which can be readily identified for a specific test, e.g.,
the maximum percentage of glass breakage in the glass washer. The inclusion of an arbitrary
value for these criteria can prove useful in the first draft, with a final value developed from the
consensus of the reviewers.
Project Specific Information
It is sometimes useful to include additional sections which elaborate upon specific aspects of
the validation effort. These sections can include detailed descriptions of the validation approach
and might be included only if the subject is complex and/or critical to the approval of the facility.
Examples of the types of subjects which might be addressed in this manner are:
computerized systems, lyophilization, cleaning, filtration, or isolation. The inclusion of this type
of detail is optional, and is the choice of those leading the particular project. For a very simple
project with no unusual features, or unconventional approaches there might be no need to
include any project specific information. Where present, these sections can be as varied in
format to accommodate the information which must be presented to the reader. A project which
has a heavily reliance on computerized controls might highlight the various systems which are
part of the project and outline the approaches to be utilized, this might be considered a mini-
plan within the overall plan. For a project with a large number of formulations to be validated, a
matrix might be included outlining the rationale for selection of the products which will support
others of similar process, strength, formulation, etc.
Standard Operating Procedures & Test Methods
The operation of a compliant facility requires the establishment of standard operating
procedures which define how the various activities are to be accomplished. The validation
master plan can incorporate SOP’s in two different fashions. SOP’s which are needed for the
execution of the validation effort can be included as attachments to the plan. Typical issues
which might be addressed in this manner would include calibration, change control, training, etc.
This inclusion increases the prominence of these essential procedures. Where the master plan
is being developed in support of new construction or new technologies, the identification of the
SOPs needed is a useful adjunct to the plan. A listing of the necessary SOP’s can be beneficial
in identifying those SOP’s which must be available prior to the I/OQ phase of the project, as well
as those which must be validated in a PQ activity. The development of an SOP list at an early
project stage allows ample time for the development of the drafts prior to their use in the I/OQ
and PQ efforts to follow. The listing can be divided into categories indicating the general area,
i.e., engineering, production, quality control, etc., which is responsible for developing and
maintaining the procedures. The inclusion of the SOP list in the master plan serves to alert
management that resources must be provided to insure their development in a timely fashion.
Closely related to the operating procedures are the sampling and test methods needed to
support both the initial qualification / validation effort and the eventual operation of the facility.
Where these are needed for the specific project, they should be treated in a manner similar to
the SOPs.
Document Formats
The qualification / validation of a new facility may be the first large scale validation effort which a
emerging firm may undertake. To ensure consistency in the documentation, the master plan
can be used to establish the formats for the various compliance documents which will be
generated. Documents which might need definition in the plan include: qualification protocols,
validation protocols, validation reports, standard operating procedures, and test methods. For
an established firm this section can usually be omitted. The inclusion of document formats is
necessary when a firm works with outside contractors for the development and/or execution of
the qualification / validation tasks.
Planning and Scheduling
After the identification of the various qualification / validation activities which are required to
bring the project through to completion, it is common to develop some form of a project
schedule which defines the sequence of activities which will be followed. For a simple project
with only a limited number of activities, this could easily be in the form of a narrative description.
As the scope of the project increases, the use of computerized project management software
such as Microsoft Project, or XXXXX Primavera is generally necessary to facilitate the planning
process. The key to this is the identification of the relationships between the various activities.
It is usually necessary to identify the activities which must precede and follow a particular
activity.
Consider the prerequisites to the PQ of a stopper washer, it must follow the OQ of the washer
and also an approved PQ protocol. Moving farther back in the project, the start of the washer
OQ, requires OQ protocol approval, IQ completion, clean steam, WFI and compressed air
availability. The activities which follow the stopper PQ might include: stopper washing PQ
report, sterilizer PQ, media fills, etc. This type of analysis should be carried out for each
activity in the project identifying each of their predecessors and successors. It is useful to break
the project into smaller elements in the development of the plan including any documentation
tasks and approvals. Aside from the obvious tasks which could be identified in any project,
additional tasks which may be incorporated are: start-up and commissioning, calibration, test &
balance and certification of classified environments, and laboratory analysis. The validation
activities should be integrated with the construction schedule to the extent possible to insure
that the duration of the project can be minimized. In many projects, some of the early
qualification tasks can be executed while the latter phases of the construction are being
completed. For instance, the installation qualification of utility systems is usually best performed
shortly after the completion of its physical installation in the absence on insulation, ceilings, etc.
After all of the tasks and their relationships have been identified, details of the project tasks
should be added such as expected task duration, required personnel support [usually broken
down by skill or discipline], required validation equipment, etc. Once the duration of the
individual tasks has been entered, the expected execution approach can be best visualized
graphically in a critical path diagram or bar chart. The overall project execution time line may
benefit from several iterations in which adjustments are made to task prerequisites, successors,
durations, and resource requirements. At some point the execution schedule is finalized, and
can be included in the master plan.
The project management software includes various views, and an wide range of reports can be
generated. These reports can provide information on overall manpower requirements,
manpower requirements by skill or craft, manpower requirements by schedule period and others
as well. It can also provide an estimate of overall project cost and duration, information of
importance to the firms’ management.
The completion of the draft execution schedule represents the last element of the plan, but
should not be the last use of the schedule. Properly managed validation projects utilize the
project management software to track progress against the schedule and adjust resources as
necessary to minimize delays in project completion. The validation execution phase can be
managed more easily through the proper use of project management software.
Approvals
Validation master plans are usually formally approved by the individuals responsible for the
resources which will execute the project. The inclusion of an approval process for master plans
has two meanings, first, it signifies the acceptance of the approaches for the project effort as
described within, and second, it acknowledges that the identified responsibilities within the plan
will be provided as needed. The approval process for a master plan can be lengthy, and usually
involves several drafts submitted for comment, and in later stages meetings at which the plan is
reviewed and discussed.
During and After the Project
Having developed a validation master plan for the project, what should be done with it after its
formal approval during the execution of the project and after its completion? Perhaps the worst
thing which can be done with the plan is to treat it as a historical document and never refer to it
again. The early stages of this effort outlined some of the possible benefits of the plan which
are possible. In order to realize these benefits, the plan must be kept current with any changes
in the information used to develop it or embodied within it. Thus any changes in the various
descriptions, and/or validation approaches should be incorporated into the plan. Thus upon
completion of the plan, it still provides a complete and accurate synopsis of the entire validation
effort as it actually happened. Some firms have chosen to maintain the plan current with
subsequent modifications to the facility, and are thus able to provide a master plan for the
facility which reflects the present circumstances of the facility or project. This can extend the life
of the plan through the operational life of the facility if desired.
Validation Master Summary
For the majority of firms which utilize master plans, the preceding section concludes their
utilization of validation master planning activities. There is however one further application of
the concept which can provide additional advantages to the firms that have chosen to utilize it.
This is the development of a validation master summary, which has the same relationship to the
master plan that a validation report has to the protocol which it responds to. To adapt the words
of Charles Dickens, if the validation master plan can be considered “the ghost of validations yet
to come”, the n the master summary can be termed “the ghost of validations past”. The
validation master summary is structured similarly to the master plan with typical sections
headings: introduction, facility / process / product description (essentially identical to that
provided in the master plan), a listing of validated systems, equipment, processes and products,
summary descriptions of the qualification / validation of the various systems, equipment,
processes and products with key data included, and a listing of the validated standard operating
procedures. The reader is provided with all of the descriptive information that is provided in
the master plan, but the inclusion of key results increases its utility enormously over the master
plan. Once completed the validation summary affords all of the benefits which can be attributed
to the master plan, yet has the additional benefit of providing answers rather than questions. To
be fully useful the master summary must be maintained current with any modifications to the
facility, equipment or systems.
Conclusion
This effort has summarized the essential elements of validation master planning, including hints
on how it can be prepared and utilized to maximum advantage. While not mandated by any
regulation, it can certainly be useful in supporting the validation of facilities, systems,
equipment, processes and products. If I can leave the reader with aspects of the validation
master plan which can have a lasting impact on their own efforts, I would emphasize the
importance of the including quantitative acceptance criteria and focusing on the product
attributes.
Acknowledgements
This effort would not have been possible without the input of many individuals who have
engaged the author to prepare master plans and or summaries for them. I must also
acknowledge, Gail Sofer of BioReliance who after asking me to write this document, had the
confidence to allow me to write it without concern as to whether I would actually meet the
required deadline. Lastly, I must again acknowledge Phil DeSantis, whose words I heard in my
head as I developed the text. This is most certainly as much Phil’s work as it is my own. I value
his ideas, energy and most of all his friendship.
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Master transfer.pdf

  • 1. See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/294240657 Master planning and validation. Part 2: System definition Article in BioPharm · April 2000 CITATIONS 0 READS 1,310 1 author: James Agalloco Agalloco & Associates Inc. 125 PUBLICATIONS 581 CITATIONS SEE PROFILE All content following this page was uploaded by James Agalloco on 30 October 2018. The user has requested enhancement of the downloaded file.
  • 2. Master Planning & Validation James Agalloco Agalloco & Associates Acknowledgment The author is deeply indebted to Mr. Phil DeSantis of Fluor Daniel, who could easily be listed as a second author on this entire effort. The many discussions Phil and I have had over the past 15 years on the subject of validation in general, and more narrowly the management of it have formed the basis for much of what is included in this effort. In many ways this effort is as much Phil’s as it is my own. Phil was also assisted this author by reviewing the early drafts prior to submission. Introduction Master planning is an activity which utilizes project management tools to assist in the development and execution of a validation project activity. It incorporates elements of project definition, coordination, administration, scheduling and budgeting to assist the validation project team in fulfilling the validation requirements. Some in the industry have gone so far as to suggest it is a CGMP requirement for capital projects executed in the healthcare industry. To this writer that view seems a bit extreme, master plans while extremely useful are not required by any existing regulation, nor should they be. There existence is not a guarantee of success, nor is their absence a predictor of failure. There are many instances where the absence of a sound master plan has been detrimental to the project, and perhaps an equal number where the plan provided no meaningful advantage to the firm. The master plan should be considered as a management tool, to be used like every other tool, for the appropriate task at the appropriate time. This effort will address various aspects of master planning, with the hope that the insights provided will be of some benefit to the reader in the use of this tool. Terminology Master planning, could also be termed validation master planning, validation project planning or validation planning. The specific name for it is largely irrelevant [though there are some who would argue that a master plan includes lesser documents termed, project or task plans]. What is essential to remember that it is a means to organize the various activities which culminate in the validation of a specific project, product or system. Recognizing that validation projects can substantially vary in scope and complexity should suggest that master plans will vary similarly. The best plan is one that is tailored to the project specific management requirements of the project, and while there are some common templates in use, it would impossible for a generic plan or template to meet the needs of every possible project. For this reason, some practitioners have chosen to define their planing tools more narrowly, with a single master validation plan, supported by project plans. This type of formality may be beneficial to some, but it is largely a decision made by a specific firm or firms, and should not be considered a universal practice. What is important is not what the tool is called, but rather how it is applied, i.e., to loosen a bolt, a wrench is often used, but specifying the type of wrench does not change the task required.
  • 3. Master Planning Adages The nice thing about not planning is that failure comes as a surprise. If you don’t know where you are going, you’re likely to end up someplace else Prior planning prevents p--- poor performance Plan Ahead Why Develop a Validation Master Plan? The answer to this has already been already given in the introduction - master planning is an activity which utilizes project management tools to assist in the development and execution of a validation activity. Within this overall definition, there are numerous advantages that a plan can provide both during the validation project execution and later during the operation of the facility, system, process or equipment. Some of these are outlined below: Structures Validation Activities - The various tasks necessary for the validation are assembled in a logical manner to facilitate the identification of project milestones, critical path, identification of resources, etc. An unordered pile of validation protocols provides some of the same information, but without ensuring that related activities are considered in proper sequence, e.g., feed water must be available to feed the clean steam, clean steam must be available to supply the autoclave, the autoclave must be validated to sterilize the parts, the parts must be sterile to perform the media fill. Other protocols might fit together in a parallel arrangement, e.g., stopper sterilization, container heat depyrogenation and product filtration sterilization are all required before filling sterile products. The master planning effort can help ensure that the various tasks associated are identified, organized and executed in a manner that minimizes the project time line, while maximizing resource [materials, equipment, personnel and funds] utilization. Project Familiarization - In any sizable validation project, there will be individuals who will need to gain reasonable familiarity with the project within a brief period of time. A sound master plan can enable individuals to gain that knowledge quickly. It can be used with both internal and external personnel who join the effort partway through its completion, or even with individuals whose duties are only peripherally affected but who require some overall project knowledge. Individuals hired after the completion of the project can gain rapid insight into the project and facility in the descriptive parts of the plan. Management Introduction - Senior management of the firm can use the plan to understand the scope of the validation effort, and to gauge the progress made towards completion against it. The plan provides sufficient overview information to ease their education in the nuances of the project. Where the plan includes budgetary and schedule information [just as included in capital project plans], senior management will have a greater awareness of the business aspects of the validation effort. Regulatory Interaction - The type of project familiarization possible through the availability of a plan can be used to advantage with regulators. The plan can convey to the inspector the scope of the effort, and ease their concerns regarding possible oversight on the part of the firm. Pieces of the plan can be used in initial regulatory
  • 4. discussions with regulators to assess their acceptance of the firm’s intended validation approach. This is of particular benefit, where the firm’s validation proposed validation approach is novel or potentially controversial, by opening a dialogue early in the project. Convertible into Drug Master File / New Drug Application - The descriptive parts of a validation master plan are quite to the type of information provided in a DMF or CMC section of an NDA. The effort expended in a facility master plan can often be reused with only minimal reformatting in these other regulatory documents. Useful with 3rd Parties - Validation master plans have been used in the solicitation of bids for validation project execution. As the plan delineates the full scope of the validation effort, validation services contractors can use it to provide bids to the project owner for the execution of some or all of the tasks. It can also be used in discussions with firms who are considering using the facility as a contract manufacturing site. Validation Program Foundation - Where a firm is building its first CGMP facility, the validation master plan can serve as the initial foundation for the organization’s validation program, both for this project and others to follow. It can define templates, methods, and procedures which will guide the firm in later projects. Since the construction of a CGMP facility may represent the first time a firm may have to execute a large number of validation activities, it can provide the framework for all subsequent validation efforts the company might undertake. Resource Planning & Scheduling - Project planning in the form of Gant or Critical Path Analysis charts are often developed in conjunction with a capital project master plan. These can be used in the management of the validation activities, and assist the firm in allocation of resources. These tools can be used both during the initial planning of the validation effort and later on during the execution of the protocols. Protocol / Report Outlines - Master plan normally include substantial information on the validation requirements which must be satisfied. The plan can also define such aspects as format, structure, approvals, etc. for the validation project for those firms which have not yet established their validation program. This is also necessary useful when working with outside contractors. Eases Protocol Preparation - The master plan can provide specific details which can be inserted into the validation protocols. By providing details requirements at early stages of the project, the design of the facility and systems can be modified to ensure that the validation expectations can be readily fulfilled. The extent to which the master plan provides definitive criteria for the various validation to be performed, will determine its utility for this purpose. If the plan is heavily detailed, the protocol preparation will be eased. In the absence of clear requirements in the plan, the protocol preparation effort will of necessity have to be more extensive. The development of a detailed master plan early in the project can be used to shift a portion of the validation workload to this earlier period in the project when the validation resources are more available. Procedure Definition - A common element of many plans is the identification of the operating procedures necessary to operate the facility or system once validated. This is especially important for new company’s where the majority of these procedures must be developed for the first time. In some instances, certain key procedures such as calibration, training, etc., are included in the master plan. Identification of SOPs at this
  • 5. early stage alerts management to the need for resources to develop them in a timely manner. What Types of Plans are Possible? Validation plans can encompass a variety of project scopes, ranging from a plan drawn to assist an entire corporation with multiple products and facilities, to those focusing on a single project of a far smaller scale. Corporate - This type of plan would encompass the overall program for a corporation, which for a large organization might include multiple products at multiple sites. For a smaller company, this type of plan might be comparable to what a larger firm might implement for a single site. By its very nature, this type of plan tends to be more general in nature and might be more of a validation policy statement than an actual validation plan. Site - This plan addresses the activities performed at a single location, and could certainly vary with the size of the site. The large multi-national companies often have sites with multiple production and developmental activities. Thus a plan for a single site of this type might be substantially more complex than a corporate plan for a smaller firm. Project / Facility - A plan developed for a single project or facility is perhaps most common. This would define the validation requirements for a single production or developmental facility. The larger companies in our industry frequently make investments in new facilities to support the production of a major new product. Rather than incorporate these operations into existing operating areas, the advantage of a new facility is the ability to tailor the design to meet the specific requirements of the new product. This type of investment is also likely when a firm first establishes a commercial scale facility for its products, as might be the case with a biotechnology firm awaiting approval of their first product. R&D areas and pilot plants will have their validation programs established in a plan of this type. Product - A product based plan might be very similar to that developed for a project or facility, with the primary difference that this type of plan would focus on the validation efforts supporting a single product, which might be produced in a series of steps and processes encompassing multiple facilities, multiple sites, or even multiple corporations. Activity - A plan written for an activity would be one established to structure the validation of a particular type. An activity focused validation plan could be written for cleaning, terminal sterilization or analytical methods.
  • 6. How Large Should a Master Plan Be? It might appear from reviewing the various types listed above that plans could vary from a relatively brief document addressing a single product or activity, to a far more extensive document covering the programs at a large multi-national organization. That however is not the case, master validation plans should be essentially the same size with varying levels of detail. A plan for a multi-national would of necessity be fairly general in nature, and as mentioned previously might be more of a validation policy or position statement, covering the subject in a fairly general fashion. At the other end of the spectrum, a plan targeted to a single product or activity would be far more detailed, and might summarize many of the key criteria to be met in the validation effort. In the author’s experience the most effective plans are approximately 50 to 75 pages long, including the same types of information with varying amounts of detail depending the goals of the plan. Phil DeSantis likes to recommend that a plan be readable in a single sitting, suggesting that it require no more than 1 to 1½ hours to read in its entirety. Having seen master plans which extend to multiple volumes covering hundreds of pages, which are nothing more than a compilation of protocols, I certainly concur that it is better to err on the side of brevity than to drone on endlessly attempting to provide every nuance of detail. A extremely large plan is difficult to be use effectively and much more difficult to maintain current. It is certainly acceptable to take a larger project and divide the validation plan into several subsections. The overall validation plan might be for the facility proper, and it would introduce the subordinate plans which could address such aspects as control systems or cleaning validation. The subordinate plans would address only a single subject and could presumably be somewhat more compact as a result. NOTE: In the rest of the document, the assumption is made that the type of plan being considered is for a project, facility or product as this is perhaps the most common application of master planning and illustrates the concepts and practices best. When is a Master Plan Not Required? First it must be recognized that there are no regulations which mandate that a firm have a validation plan. Despite what one may here at conferences or papers, master plans are not a CGMP requirement. The more complex the project the more a plan can be valuable in providing some degree of structure to the effort. A very simple project could certainly be completed successfully without a plan. As the individual responsible for organizing the validation of one of the first heavily automated parenteral facilities in the mid-1980's, no validation master plan was developed, at least not in the formal sense. Over the course of the project we developed a number of documents and used a variety of management tools to organize our work, but there was nothing prepared which resembled a validation master plan. Our effort was ultimately successful, for what was and still is one of the larger facilities of its kind. Clearly it is possible to complete a complex validation project without a plan. Despite what I’ve just written, I would certainly agree that if I were to undertake a similar scale project today, or even a much smaller project, I would prefer to develop a validation master plan for that effort. There is a point at which the need for a plan can certainly be questioned. In several recent projects I have been required by my client to prepare a master plan for the project. In one case, the total number of protocols which had to be developed for the project was only 6 encompassing both I/OQ and PQ activities. It appeared to me that the scope of the project did not warrant the development of a master plan, as there appeared to be very little chance of the project overwhelming anyone’s ability to comprehend what was intended or how it was to be executed. Nevertheless, this firm had a corporate policy which mandated that for validation
  • 7. projects in which an outside firm was utilized that a master planning document be prepared. I conceded the point and wrote the plan. It was the briefest I have ever prepared, a mere 17 pages, and I should also note was something which I never referred to during the entire project execution. I did not ask the firm if they would have prepared a plan had they performed the project with internal resources, I fear that they might have. A parallel I might draw is the preparation of a shopping list before visiting the market. If I’m only going for few items, I will trust my memory and not prepare one before I shop. As the number of items I require increases, the more likely I am to prepare a list, and actually use it during the course of my shopping. A validation master plan can be looked at similarly, for simple project the effort expended in preparing, reviewing and approving a master plan may have no justifiable return. At what point this occurs for a project will depend upon the capabilities of the firm and the experience of their staff. When Should a Master Plan be Written? Unlike the preceding question, there is most certainly a preferred point in a project at which the preparation of a validation plan is most advantageous. This occurs after the firm has established some clear objectives for its project. It must be able to answer some simple questions as to the scope, size and goals of the project. This generally happens when a firm has completed its preliminary design process. The original wish list of project goals will have been weaned down to some agreed upon features which the project must include. This is the optimum time for plan development, the narrowing of project options that has occurred in preliminary design, allows the plan to be written with a firm sense of what the project objectives are. If it is prepared before this point, there are likely to be a series of drafts reflecting the changing nature of the project. It is preferable to wait until agreement has been reached on the scope of the project, to prevent this. If the plan is prepared concurrent with the start of detailed design for the project, the master plan can be used to help finalize that design, while the availability of some design information makes the preparation of a meaningful plan possible. Developed early enough the validation plan can alert the design team to the need for sample points in the water systems, access points for thermocouples into pressure vessels for SIP, and similar items. If the plan is developed after the completion of detailed design, the opportunity to identify these types of items may be lost, but provided the plan is available prior to the start of the validation effort it can still prove extremely useful. I have heard instances where a firm has prepare a “validation master plan” retrospectively. That is after the facility was completed, but prior to regulatory inspection. While hardly a planning document in the sense that it was prepared after the activities were completed, it still enabled the firm to realize some of the benefits of a plan prepared in the more conventional or prospective manner. The firm was able to use the “plan” as part of their regulatory interaction to good advantage. While it missed the ability to use the plan in managing their validation effort, they were still able to use it effectively to manage their regulatory interaction. Of course the advantages related to having the plan for a completed facility were also possible Who Should Write the Plan? Validation plans are best written by a single individual who possesses a knowledge of the project and is sufficiently well versed in the validation requirements for the project. A single author should be able to structure the document with a consistent level of detail, with minimal redundancy far easier than a team. This person could be an employee of the firm, a consultant, or an employee of a engineering / architectural firm. Regardless who is the author, it is essential that the plan extend into the performance qualification of the product / processes for
  • 8. which the project is intended. This aspect of the validation is the part which draws the most attention from regulators, and is sometimes the most neglected piece. Whomever prepares the plan must be conversant enough in validation of these production processes to insure that these are addressed in sufficient detail.. What Information is Needed to Prepare a Master Plan? Before preparing a master plan, the following information should be assembled. The higher the accuracy of this information, the easier the task of actually writing the plan will be. Facility Layout - A layout of the facility helps define the relationship between the various operating, support and other areas of the facility. The layout helps support the suitability of material, component, personnel and equipment flows. Depending upon the usage of the facility, the layout can have a profound impact on the suitability of the facility for its intended purpose. The layout is not a construction drawing and may be more of a sketch than a final document. Process Description - An important element of any production facility is a description of the process(es) to be performed within it. This could include: fermentation, and purification for a biotechnology product; the unit operations possible in a multi-product dosage form facility, or the chemical reactions which are utilized in an bulk pharmaceutical plant. For a single product plant, this description should be detailed enough to provide a complete understanding of the process involved in it’s manufacture. For larger scale facilities, the description should become more of an outline of production capabilities rather than the specifics of any individual process. For developmental facilities, the capabilities of the facility are summarized to establish the flexible nature of the use to which the facility will be put. A visual presentation of this information can prove useful in multi-step processes. Product Description - Details of the product(s) to be manufactured within the facility are also included. Again the level of detail will vary with the number of products being produced. This section would be omitted in a developmental facility where the production of any individual product or product type is more incidental than mandatory. Equipment List - The focus of the qualification / validation effort is often the equipment which is installed within the facility. This list can be further subdivided by process or location within the facility if necessary. Specifics of manufacturer, model, capacity, etc. if known can also be beneficial. This list is usually the result of having finalized the process / product for which the facility is to be utilized. Equipment which is always operated as an assembly, e.g., a packaging line, is more commonly identified as a single entry rather than being broken down into its component parts. Utility List - For larger facilities, where the number of utility systems is large, then a separate list of utilities to be provided can be beneficial. Once the process equipment has been identified, the development of the utilities needed to support them can be developed. In smaller facilities, this list is better integrated with the equipment list. As suggested with the process equipment, it is preferable to identify each utility system, e.g., the water for injection system including pretreatment, still, storage tank and distribution system than to address the equipment individually.
  • 9. Controlled Environment Requirements - Facilities which have classified and/or controlled environments should have these identified in the plan as well. These should be identified on the facility layout. The elements of the HVAC or other systems which support these environments should be known as well. Process Control - Where the facility is to be supported by a control system, as might be found in a BPC or biotech facility to support the key production processes, then some elements of the any proposed control system design would be provided. This section should be omitted where an overall control system is not present. Aspects of computer controlled equipment would then be included within the equipment / utility descriptions proper. Project Schedule - Planning the execution of a validation effort must consider the overall schedule for the product. A project which is design-build will require a different validation timetable, than one which follows a more typical design-bid-contract-build procedure. The quality of the plan which is developed is dependent upon the accuracy of the information provided to the author. This oftentimes implies a trade off, writing a plan early in the design phase allows more time for plan development, but will likely mean that less specific information will be available to the author. Deferring the plan development, allows for more detailed information to be communicated to the author but minimizes the opportunity to integrate validation concerns into the design. The earlier discussion on the timing of plan development should also be considered in this same context. What is Included in a Master Plan? The following are typical sections of a master plan. The order of presentation is flexible as there are no standards which mandate any specific order. Introduction - Introduction to the project scope, location, and timing. Includes responsibilities for protocol, SOP, report and other documentation preparation and approval. Identifies who is responsible for the various activities. A general validation SOP or policy statement is frequently included. Facility/Process/Product Description - A concise but complete description of the entire project is provided. It will provide information on: materials of construction; layout and flow of personnel, materials, and components; description of utility and support systems; brief description of the processes to be performed and products to be made in the facility. Major equipment is described with minimal details. It generally includes drawings of the facility and process flow diagrams. Information on the product(s) to be manufactured is also provided. This section can be divided into 3 parts for larger scale projects. Automation / Process Control Considerations - Computerized information, laboratory and process control systems are described in sufficient detail to delineate the validation requirements. This section may be omitted if the level of automation is minimal. This information can also be included in the equipment section where automation is limited to equipment control.
  • 10. List of Systems / Processes / Products to be Qualified / Validated - This section is sometimes referred to as system definition. Equipment, systems and products are listed in a matrix format which describes the extent of validation required [i.e. IQ, OQ, or PQ] as part of the project. Additional breakout of computerized, cleaning and sterilization validation requirements can be added if the project is complex enough. Protocol Outlines / Acceptance Criteria - The overall protocol requirements and acceptance criteria [general and specific] for the items listed in the prior section are provided. Emphasis should be on quantitative criteria throughout. Project Specific Issues - This section is included where there are elements of the validation effort which bear greater clarification or emphasis. Subjects which the author has addressed in this manner include: computerized systems, cleaning, isolation technology, and lyophilization. Document Formats - The format to be used for protocols, reports and procedures is described. This is particularly useful for companies embarking on their first CGMP facility and for any project in which multiple organizations will be executing a portion of the overall validation effort. Standard Operating Procedures - List of SOP's [new or existing] necessary to operate the facility. The inclusion of this list serves to highlight the number of procedures required to operate and maintain the facility. Planning & Schedules - An estimate of the staffing requirements to complete the validation effort described in the plan. A preliminary schedule of required activities is prepared to help estimate appropriate manning levels. Plan Introduction This section of the plan serves to explain the intentions of the project. It describes the what, when, where, why, who and how of the project. This section is typically less than a page and broadly defines the scope of the project. This section should provide a brief summary of all of the following sections. Descriptions The descriptive part of the plan can include all three elements: facility , process and product. In developmental projects, the absence of a defined product or process precludes any real details in these areas. In those instances, the description of process and product should speak to the capabilities of the facility, in terms such as: non-sterile coated and uncoated tablets and capsules in batch sizes up to 50 kg. In commercial plants, the product and process sections should be far more complete. In the author’s experience this is one area which is frequently inadequate in many plans. There is a tendency on the part of some plan preparers to think of the validation as it relates only to the equipment and systems, and give only minimal, if any attention to the processes and products which those equipment and utility systems are expected to produce. This leads the firm through fairly straightforward execution of their installation and operational qualification, but with little insight into how the always critical performance qualification activities which follow are to be executed.
  • 11. Facility Description - Facility descriptions are usually included in master plans, though plans written for aspects such as cleaning and analytical methods might omit this information. Included in this section would be a sketch or single line drawing showing the overall facility layout with major equipment and classified environments indicated directly on it. This diagram is not a mechanical drawing, the additional information provided on a construction drawing is not necessary for the purposes of master planning, and even tends to confuse the description somewhat. The diagram can be supplemented with a series of overlays which depict personnel / material / component and equipment flows through the facility. A listing of classified and controlled environments can be included where provided. This can be augmented with diagram(s) depicting and environmentally controlled or limited access zones or areas. For facilities where microbial control is critical, information on the materials of construction should be included. The emphasis in this section should be visual rather than written, the information is often best conveyed in simple diagrams or sketches. Process Description - The process description should explain in words the processes to be performed within the facility. This should identify major process steps in their proper sequence. For a tablet process, these might be identified as weighing, blending, granulation, milling, final blending and compressing. A biotech process might be described as cell bank harvest, cell propagation, fermentation, cell lysis, extraction, ultrafiltration, chromatography and bulk packaging. In a BPC facility, the various steps of reaction chemistry would be described. The process description can be presented in various formats: written narratives, annotated block diagrams, or process flow diagrams. The inclusion of critical parameters (if known) serves to increase the utility of the descriptive information. Where multiple products are manufactured, the process for each can be provided. In parenteral and biotech facilities, where control of microorganism of a major importance, descriptions of the major utility systems, especially Water for Injection, and the primary sterilization equipment; steam sterilizers, dry heat tunnels and ovens, etc. is commonplace. Product Description - An portion of the master planning effort which is often under represented is the product description. It should include information on product type(s), production volume [optional], batch size(s), formulation [optional], and important product features (color, viscosity, flavor, etc.) [optional], package(s). Other aspects to include are product solubility, operator safety and handling aspects, and stability (in the presence of heat, moisture, light, and air). These last elements may have an impact on the validation program: solubility of the materials impacts the cleaning validation effort; safety and handling concerns may mandate facility changes to protect the workers and the environment; while stability (in-process and/or finished goods) will dictate specialized requirements to mitigate potential degradation of the materials. Other Descriptions - Detailed descriptions of other types are certainly possible. In past plans the author has included sections on cleaning procedures, control systems and isolation technology. The need for such descriptions is dependent upon the specific elements of the particular project which requires additional attention. Systems Definition This is the core of the plan, in which the scope of the validation effort can be rapidly understood. The centerpiece of this section is often a table which lists the systems, equipment, processes and products and then identifies whether they are subject to commissioning, qualification
  • 12. and/or validation. In this author’s opinion, too many master plans do a incomplete job in this area, they restrict the list to physical items of equipment, or facility elements, and omit such critical aspects as sanitization, cleaning, production processes and products. This is unfortunate, as the true intent of the validation master plan is to support the start of production of a product, not to document a construction effort. Regulators and owners should only be concerned with equipment and facilities aspects to the extent that they can impact the identity, quality, purity and efficacy of the materials being produced. Plans which address only the equipment and facilities elements are perhaps more accurately termed “qualification master plans”. Only when they include supportive guidance on the processes and production methods for the product(s) being manufactured can they be considered true “validation master plans”. Where these aspects are minimized, or worse yet ignored, the utility of the master plan is severely diminished. Additional utility for this effort can be obtained through an expansion in the categories beyond merely commissioning, qualification and validation. By adding to the number of columns such aspects as cleaning, sterilization, control systems, the full scope of the effort can be more readily understood. The following table is an example of a listing which includes enhancements over those typically found. Equipment, Systems and Procedures to be Validated East Antartica, Sterile Products Facility Description Commiss ioning I/OQ PQ Sterilize Clean Control System Fixed Manufacturing Tank X X X Fixed Holding Tank X X X X Portable Tanks X X X Homogenizer X X X X X CIP System X X Vial Washer X X X Depyrogenation Tunnel X X X Accumulation Table X Vial Filler/Stoppering X X X X X Vial Capper X X X X Vial Inspection X Labeler/Label Verification X X X Bail Bander X Vial Accumulator X Tray Maker X Overwrapper X
  • 13. Palletizer X Case Packer X Stopper Processor X X X X Steam Sterilizer X X X Parts Cabinet Washer X X Ultrasonic Parts Washer X X X Autoclave Bag Sealers X X Calibration Equipment X Filter Integrity Apparatus X X HEPA Vacuum Cleaners X Clean Steam System X X X WFI System X X X Deionized Water System X X HVAC System #1 - Aseptic Core X X X HVAC System #2 - Preparations Area X X X Laminar Air Flow Hoods X X HVAC System #3 - Unclassed areas X Automated Air Locks X X Fixed Environmental Monitoring System X X Portable Environmental Monitoring Units X Building Monitoring System X X X Compressed Air System X X X Plant Steam X City Water System X Sanitary Drainage System X Process Drainage System X Condensate Return System X Product 1 Solution X X
  • 14. Product 2 Solution X X Product 3 Suspension X X Gowning Procedures X Manual Inspection of Vials X Media Fills X Manual Cleaning X X Sanitization X As this table represents the centerpiece of the plan, some clarification of its design and use is necessary to fully understand it and the plan which is built around it. 1. Note how equipment items for which cleaning validation must be performed are identified in a column designated for that purpose. Similarly, the inclusion of the products and such activities as vial inspection, and media fills serves as a reminder that their validation must also be considered in the project scope. The homogenizer is the subject of several different PQ efforts. Its sterilization, cleaning, control system and performance in properly sizing the drug particles must all be validated. Considering that each of these activities may be defined in a separate protocol, the inclusion of the additional columns helps clarify the validation requirements more clearly than had they been lumped together. 2. Note also that there are systems and equipment indicated in the list which are not subject to formal installation / operational qualification. These items are commissioned, an exercise substantially less formal than qualification which serves merely to confirm that the system or equipment has been installed properly or meets its very limited operational criteria. Commissioning is generally done without formally approved protocols and is appropriate for elements of the facility which have minimal impact on key product quality attributes. 3. The inclusion of systems in the table comprised of many different small equipment items might suggest that an overall I/OQ be prepared. That is certainly a option for a small system, but it is preferable to prepare individual I/OQ documents for the individual items. Thus at the I/OQ stage a water system would system would have separate I/OQ’s for each piece of equipment in the pretreatment system, i.e.; sand filter, carbon filter, deionization beds, ultra filter, etc., During the PQ of this system, it would be perhaps easier to prepare a single protocol addressing the sampling throughout the pretreatment, storage and distribution systems. The table merely serves to indicate what level of documentation the system will be subjected to rather than define exactly how that documentation is to be assembled. 4. A number of the required PQ activities are those which support the standard operating procedures for the various equipment, systems and other activities. Draft SOP’s are validated in the PQ phases of the project. The approval of the PQ reports should be accomplished in conjunction with the approval of the SOP for the process which the PQ validates. After all, for the SOP to be approved, its requirements and conditions must be supported by validation data which confirms the acceptability of the procedure details.
  • 15. 5. The table above listed installation and operational qualification together as a single activity. Considering that in the vast majority of efforts, a system which is subject to installation qualification will also be subject to operational qualification, their identification as a common requirement is straightforward. The author’s preference is to more closely integrate them as a single activity entitled qualification, with a single protocol and a single report. Given the absence of regulatory guidance in this area, the combination of these activities is certainly acceptable. 6. The table also included a number of activities; sanitization, media fills, manual cleaning, etc. which had only a PQ stage. Their inclusion identifies that their completion is required to have a validated facility, despite the absence of a individual I/OQ activity preceding it. Each of these items should have its validation requirements defined in the specific acceptance criteria section of the plan [see later section]. General Acceptance Criteria To avoid unnecessary redundancy in master plans, a common practice is to include a section entitled general acceptance criteria. These criteria are universal and applicable to all items in the table which have that column checked. General acceptance criteria can be related to any or all of the various stages: commissioning, installation, operational or performance qualification. Depending upon the stage for which the criteria are established, these will be repeated in the appropriate protocol for each system or piece of equipment. The following are examples of typical general acceptance criteria for each stage. Commissioning - typical commissioning requirements All equipment, piping, wiring, instrumentation must be clearly identified in the field and conform to the descriptions provided in the appropriate drawing or other documentation. All piping systems shall have been cleaned to remove construction debris and such cleaning shall be documented. Installation Qualification - typical general acceptance criteria Change control on all equipment and systems in the facility shall be instituted from the start of the IQ for each item. Any changes made subsequent to the start of the IQ must be made in accord with site equipment change control procedure. For all automated systems, written or electronic [human readable] documentation of all application software shall be available. Software shall be annotated to allow for comparison to written process descriptions. A flow chart shall be supplied outlining each application software program. Operational Qualification - typical general acceptance criteria Systems and equipment must function reliably under environmental conditions approximating those of normal use. Draft written Standard Operating Procedures shall have been prepared for the operation of each system and piece of equipment. These procedures will be finalized and formally approved after completion of the PQ evaluation of each system.
  • 16. All instrumentation [indicating and recording] must be calibrated using written procedures. Calibrations shall be traceable to the appropriate national or international standards wherever possible. Performance Qualification - typical general acceptance criteria Critical operating parameters shall be independently measured and documented in each trial. Such measurements will be made with traceable instruments where possible. Systems shall perform as intended with regard to expected yields, volumes, flow rates, as described in the appropriate SOP's. Components, materials, and products processed by each system or piece of equipment shall conform to appropriate in-process or finished goods specifications. It should be recognized that some equipment and utility items in the system definition table will only have general acceptance criteria, and will only be subject to the requirements of this section. Other systems and pieces of equipment will be subject to both the general criteria, and also to criteria specific for that system. Specific Acceptance Criteria Some of the equipment listed in the system definition section of the master plan will have criteria which are unique to that system. These are defined individually for each system or equipment item. In comparison to the general acceptance criteria which as noted above are rather subjective or rule oriented, the specific criteria should be largely quantitative in nature. In this author’s opinion, the best master plans are those which include numerical requirements wherever possible. The reliance on rigorous criteria facilitates the subsequent preparation of validation protocols as the more meaningful criteria for those protocols has been already defined and embodied in the master plan. As setting acceptance limits is among the more contentious aspects of protocol preparation, moving it to the master plan stage allows more time for consensus building. The following examples are drawn from a plan the author prepared some years back: Depyrogenation Tunnel Installation Qualification 1. The HEPA filters installed in the machine shall be certified to retain a minimum of 99.97% of particles larger than 0.5 micrometer. Operational Qualification 1. Air within the tunnel shall meet FS 209 E Class 100 requirements at operating temperature [circa 330°C]. 2. The tunnel shall be able to operate properly while maintaining a maximum 0.10" H2O pressure differential from discharge to infeed. 3. The dry heat tunnel shall operate properly throughout its operating range of 0 to 100, 100 and 200 mL vials per minute. 4. The tunnel shall maintain a distribution temperature range [belt edge to belt edge] of not more than 30°C throughout its length when empty. 5. The tunnel shall maintain a distribution temperature range [belt edge to belt edge] of not more than 25°C throughout its length when full of 200 mL vials. Performance Qualification
  • 17. 1. The tunnel shall be capable of a minimum 3.0 log reduction in endotoxin content for all vial sizes. The minimum challenge level shall be 1,000 Eu/vial [recoverable]. 2. There shall be no increase in vial particulate matter content as a result of passage through the tunnel. 3. The tunnel shall maintain a penetration temperature range [belt edge to belt edge] of not more than 20°C throughout its length when full of 200 mL vials. The inclusion of quantitative criteria in the master plan is sometimes deemed an unnecessary exercise by some individuals. Their position is that such details belong in the validation protocols. In the author’s opinion, this reduces the value of the plan substantially. If one only wanted to know what was going to be commissioned, qualified or validated, the plan could consist only of the system definition table described earlier. It is only when the detailed requirements are included that a real feel for the scope of the effort can be obtained. A plan without numbers is like a chocolate chip cookie without the chocolate chips, it has the name but none of the substance which makes it what is should be. The numerical values used in this section of the plan can be drawn from a number of sources: regulatory or pharmacopieal guidance, industry guidelines, equipment specifications, vendor recommendations, design documentation, or even experience in prior or similar installations. e In preparing the specific acceptance criteria section, there will be times when there are no commonly agreed upon numerical criteria which can be readily identified for a specific test, e.g., the maximum percentage of glass breakage in the glass washer. The inclusion of an arbitrary value for these criteria can prove useful in the first draft, with a final value developed from the consensus of the reviewers. Project Specific Information It is sometimes useful to include additional sections which elaborate upon specific aspects of the validation effort. These sections can include detailed descriptions of the validation approach and might be included only if the subject is complex and/or critical to the approval of the facility. Examples of the types of subjects which might be addressed in this manner are: computerized systems, lyophilization, cleaning, filtration, or isolation. The inclusion of this type of detail is optional, and is the choice of those leading the particular project. For a very simple project with no unusual features, or unconventional approaches there might be no need to include any project specific information. Where present, these sections can be as varied in format to accommodate the information which must be presented to the reader. A project which has a heavily reliance on computerized controls might highlight the various systems which are part of the project and outline the approaches to be utilized, this might be considered a mini- plan within the overall plan. For a project with a large number of formulations to be validated, a matrix might be included outlining the rationale for selection of the products which will support others of similar process, strength, formulation, etc. Standard Operating Procedures & Test Methods The operation of a compliant facility requires the establishment of standard operating procedures which define how the various activities are to be accomplished. The validation master plan can incorporate SOP’s in two different fashions. SOP’s which are needed for the execution of the validation effort can be included as attachments to the plan. Typical issues which might be addressed in this manner would include calibration, change control, training, etc.
  • 18. This inclusion increases the prominence of these essential procedures. Where the master plan is being developed in support of new construction or new technologies, the identification of the SOPs needed is a useful adjunct to the plan. A listing of the necessary SOP’s can be beneficial in identifying those SOP’s which must be available prior to the I/OQ phase of the project, as well as those which must be validated in a PQ activity. The development of an SOP list at an early project stage allows ample time for the development of the drafts prior to their use in the I/OQ and PQ efforts to follow. The listing can be divided into categories indicating the general area, i.e., engineering, production, quality control, etc., which is responsible for developing and maintaining the procedures. The inclusion of the SOP list in the master plan serves to alert management that resources must be provided to insure their development in a timely fashion. Closely related to the operating procedures are the sampling and test methods needed to support both the initial qualification / validation effort and the eventual operation of the facility. Where these are needed for the specific project, they should be treated in a manner similar to the SOPs. Document Formats The qualification / validation of a new facility may be the first large scale validation effort which a emerging firm may undertake. To ensure consistency in the documentation, the master plan can be used to establish the formats for the various compliance documents which will be generated. Documents which might need definition in the plan include: qualification protocols, validation protocols, validation reports, standard operating procedures, and test methods. For an established firm this section can usually be omitted. The inclusion of document formats is necessary when a firm works with outside contractors for the development and/or execution of the qualification / validation tasks. Planning and Scheduling After the identification of the various qualification / validation activities which are required to bring the project through to completion, it is common to develop some form of a project schedule which defines the sequence of activities which will be followed. For a simple project with only a limited number of activities, this could easily be in the form of a narrative description. As the scope of the project increases, the use of computerized project management software such as Microsoft Project, or XXXXX Primavera is generally necessary to facilitate the planning process. The key to this is the identification of the relationships between the various activities. It is usually necessary to identify the activities which must precede and follow a particular activity. Consider the prerequisites to the PQ of a stopper washer, it must follow the OQ of the washer and also an approved PQ protocol. Moving farther back in the project, the start of the washer OQ, requires OQ protocol approval, IQ completion, clean steam, WFI and compressed air availability. The activities which follow the stopper PQ might include: stopper washing PQ report, sterilizer PQ, media fills, etc. This type of analysis should be carried out for each activity in the project identifying each of their predecessors and successors. It is useful to break the project into smaller elements in the development of the plan including any documentation tasks and approvals. Aside from the obvious tasks which could be identified in any project, additional tasks which may be incorporated are: start-up and commissioning, calibration, test & balance and certification of classified environments, and laboratory analysis. The validation activities should be integrated with the construction schedule to the extent possible to insure that the duration of the project can be minimized. In many projects, some of the early
  • 19. qualification tasks can be executed while the latter phases of the construction are being completed. For instance, the installation qualification of utility systems is usually best performed shortly after the completion of its physical installation in the absence on insulation, ceilings, etc. After all of the tasks and their relationships have been identified, details of the project tasks should be added such as expected task duration, required personnel support [usually broken down by skill or discipline], required validation equipment, etc. Once the duration of the individual tasks has been entered, the expected execution approach can be best visualized graphically in a critical path diagram or bar chart. The overall project execution time line may benefit from several iterations in which adjustments are made to task prerequisites, successors, durations, and resource requirements. At some point the execution schedule is finalized, and can be included in the master plan. The project management software includes various views, and an wide range of reports can be generated. These reports can provide information on overall manpower requirements, manpower requirements by skill or craft, manpower requirements by schedule period and others as well. It can also provide an estimate of overall project cost and duration, information of importance to the firms’ management. The completion of the draft execution schedule represents the last element of the plan, but should not be the last use of the schedule. Properly managed validation projects utilize the project management software to track progress against the schedule and adjust resources as necessary to minimize delays in project completion. The validation execution phase can be managed more easily through the proper use of project management software. Approvals Validation master plans are usually formally approved by the individuals responsible for the resources which will execute the project. The inclusion of an approval process for master plans has two meanings, first, it signifies the acceptance of the approaches for the project effort as described within, and second, it acknowledges that the identified responsibilities within the plan will be provided as needed. The approval process for a master plan can be lengthy, and usually involves several drafts submitted for comment, and in later stages meetings at which the plan is reviewed and discussed. During and After the Project Having developed a validation master plan for the project, what should be done with it after its formal approval during the execution of the project and after its completion? Perhaps the worst thing which can be done with the plan is to treat it as a historical document and never refer to it again. The early stages of this effort outlined some of the possible benefits of the plan which are possible. In order to realize these benefits, the plan must be kept current with any changes in the information used to develop it or embodied within it. Thus any changes in the various descriptions, and/or validation approaches should be incorporated into the plan. Thus upon completion of the plan, it still provides a complete and accurate synopsis of the entire validation effort as it actually happened. Some firms have chosen to maintain the plan current with subsequent modifications to the facility, and are thus able to provide a master plan for the facility which reflects the present circumstances of the facility or project. This can extend the life of the plan through the operational life of the facility if desired. Validation Master Summary
  • 20. For the majority of firms which utilize master plans, the preceding section concludes their utilization of validation master planning activities. There is however one further application of the concept which can provide additional advantages to the firms that have chosen to utilize it. This is the development of a validation master summary, which has the same relationship to the master plan that a validation report has to the protocol which it responds to. To adapt the words of Charles Dickens, if the validation master plan can be considered “the ghost of validations yet to come”, the n the master summary can be termed “the ghost of validations past”. The validation master summary is structured similarly to the master plan with typical sections headings: introduction, facility / process / product description (essentially identical to that provided in the master plan), a listing of validated systems, equipment, processes and products, summary descriptions of the qualification / validation of the various systems, equipment, processes and products with key data included, and a listing of the validated standard operating procedures. The reader is provided with all of the descriptive information that is provided in the master plan, but the inclusion of key results increases its utility enormously over the master plan. Once completed the validation summary affords all of the benefits which can be attributed to the master plan, yet has the additional benefit of providing answers rather than questions. To be fully useful the master summary must be maintained current with any modifications to the facility, equipment or systems.
  • 21. Conclusion This effort has summarized the essential elements of validation master planning, including hints on how it can be prepared and utilized to maximum advantage. While not mandated by any regulation, it can certainly be useful in supporting the validation of facilities, systems, equipment, processes and products. If I can leave the reader with aspects of the validation master plan which can have a lasting impact on their own efforts, I would emphasize the importance of the including quantitative acceptance criteria and focusing on the product attributes. Acknowledgements This effort would not have been possible without the input of many individuals who have engaged the author to prepare master plans and or summaries for them. I must also acknowledge, Gail Sofer of BioReliance who after asking me to write this document, had the confidence to allow me to write it without concern as to whether I would actually meet the required deadline. Lastly, I must again acknowledge Phil DeSantis, whose words I heard in my head as I developed the text. This is most certainly as much Phil’s work as it is my own. I value his ideas, energy and most of all his friendship. View publication stats