DELIVERING VALUE TO THE PROCESS DEVELOPMENT ORGANIZATION
THROUGH WORKFLOW INTEGRATION
by
Peter A. Clark
Applications Consultant
Aspen Technology, Inc.
Abstract
Process development organizations in modern pharmaceutical firms face the
dual challenges of making clinical supplies under tight deadlines and developing a
viable commercial manufacturing process at the same time. These two work
processes are intertwined in complex ways, and often involve the work of many
different teams.
We propose a way to meet both requirements in a parallel and coordinated
fashion, by using a carefully designed software environment to revamp the
workflow. Benefits derived include: eliminating errors and rework; improving
communications effectiveness and efficiency; promoting collaboration and
concurrency; preserving and leveraging intellectual capital to improve the quality
of the design; reducing the effort for individual tasks; and rapidly evaluating
alternatives to choose the best. The flexible architecture adapts to business needs
quickly and easily.
API Process Development –
1. Principal Work Components of Drug developing a commercially viable process to
Development manufacture the drug substance.
Figure 1 shows a simplified process Pharmaceutical Product & Process
map [1] for the development of new drugs in Development – developing a final dosage
a modern pharmaceutical firm. The solid form to administer the drug to human
lines in the figure show the material flow. patients and a commercially viable
The dashed lines represent the information pharmaceutical (formulation) process to
(process development) flow. manufacture the dosage form.
Drug Discovery – identifying drug The Supply Chains – procuring raw
substances (also called active materials (e.g. reagents, solvents, excipients
pharmaceutical ingredients, or APIs) with and coatings), converting the reagents to the
therapeutic benefits. drug substance, adding the additional
ingredients to make the dosage form,
Portfolio Management – allocating allocating the resources to make the drug
precious development resources across the substance and dosage form (planning and
range of drugs under development in the scheduling of facilities and labor), and
company. delivering the product. There are really two
distinct supply chains – one that delivers the
DELIVERING VALUE TO THE PROCESS DEVELOPMENT ORGANIZATION THROUGH
WORKFLOW INTEGRATION
by Peter A. Clark
product to clinical trials and development performance dimensions [2].
trials, and another that delivers the product
to the market. The API Segments of the Supply
Chains produce the drug substance and
Testing – planning, conducting and deliver it to Pharmaceutical R&D or
analyzing the results of toxicology studies, Pharmaceutical Manufacturing.
clinical trials and stability tests to determine
the safety, efficacy and shelf life of the drug. Quality
In this paper, we will focus our • Purity
attention on API Process Development, and
the API segment of the Supply Chain (from • Appropriate physical attributes –
raw materials through production of the drug morphology, particle size, moisture
substance). We will not discuss the other content, etc.
work components further.
Costs
2. Critical Performance Dimensions • Raw materials (reagents, solvents)
Each of our chosen work processes • Labor
has one key output, with a number of critical
Drug
API
APIProcess
ProcessDevelopment
Development
Discovery
Pharmaceutical Product & Process Development
Raw Materials Raw Materials
(Reagents, Solvents) (Reagents, Solvents)
Process Process
Concept Concept
Development
Development API
API
APIProduction
Production Manufacturing
(Pilot
(PilotPlants)
Plants)
Raw Materials Raw Materials
(Excipients, Drug (Excipients, Drug
Coatings) Substance Coatings) Substance
Portfolio Process
Development
Process Pharmaceutical
Pharmaceutical
Management Concept Concept Manufacturing
Production
Product to Clinical Trials Product to Market
Testing (Toxicology Studies, Clinical Trials)
Figure 1. Development of New Drugs
DELIVERING VALUE TO THE PROCESS DEVELOPMENT ORGANIZATION THROUGH
WORKFLOW INTEGRATION
by Peter A. Clark
Productivity 3. Key Features of the Drug Lifecycle,
Challenges Posed and Impact on
• Quantity Performance
• Timeliness We have identified five key
characteristics of the drug lifecycle that
API Process Development produces impact the critical performance dimensions
the process used to make the drug substance for Process Development. We will describe
and delivers this process to the Pilot Plant or these features, discuss the challenges they
to API Manufacturing. pose and summarize their impact on
performance.
Quality
3.1. Long Timeline and Limited
• Can make required product (meet Probabilities of Success
quality specs) at projected demand
and schedule (rate) It takes a long time – between 5 and 9
years – to move a drug from discovery to
• Runs in available equipment launch. Also, many candidates are
abandoned at various points along the cycle.
• Operable by available labor For each drug brought to market, tens of
thousands of candidates are screened in
• Clears company’s financial hurdles Discovery. Even for candidates promising
enough to file an IND and start clinical
• Safe trials, only 23% enter the market. [3]
• Robust Challenge: Few people have
experienced the entire lifecycle.
• Complies with environmental Development team members cannot rely
regulations solely on their own experience to succeed.
• Complies with FDA regulations Impact on Quality
(“validatable”)
• Team members are unaware of
Costs certain issues and alternatives
miss a better process. Decisions
• Labor costs (effort) made during process development
are frozen into the process at
• Material costs for laboratory runs
validation, and will determine its
Productivity performance over its life span –
hopefully ten years or more.
• Time to complete development work
(time to market) • Errors in applying “best practices” /
guidelines
DELIVERING VALUE TO THE PROCESS DEVELOPMENT ORGANIZATION THROUGH
WORKFLOW INTEGRATION
by Peter A. Clark
Impact on Costs labor. Even runs at lab scale can take
considerable time, particularly when the
• Effort to find and understand process includes slow reactions,
available information fermentations or chromatography.
• Effort to find expertise and Challenge: Tight timelines,
understand guidance from experts escalating demand for drug substance
and limited development resources
• Effort spent “reinventing the wheel” conflict with the need to develop the best
– work and troubleshooting that possible process
could have been avoided with
appropriate knowledge in hand Impact on Quality
Impact on Productivity • Few alternatives examined miss a
better process.
• Timing slips as problems arise and
troubleshooting occurs Impact on Costs
3.2. Clinical Demands Dictate • Conducting more runs increases
Development Efforts materials and labor costs
The interactions between Process Impact on Productivity
Development and the Clinical Supply Chain
are complex. Often, each campaign to make • Conducting more runs can extend the
clinical supplies for a given drug uses a timeline
different process, for two reasons. First, as
the drug progresses from Phase I to Phase III 3.3. Diverse Range of Activities Involved
trials, it is given to more patients over longer
periods, so we must scale up the process to Broadly speaking, we can group the
meet the increasing demands. Second, activities involved in the API lifecycle into
development work continues to improve the four main steps:
process, to ensure that the process ultimately
delivered to manufacturing meets the critical • Propose a Process Concept – The
quality dimensions. At the same time, each process concept includes the materials
process delivered to the pilot plant must be used and quantities, chemical route
able to meet clinical demands for quality, (reactions) and separations, and
quantity and schedule, be safe, and comply operating procedure. It is an idealization
with environmental regulations. – free from equipment details and
limitations – often written on the basis of
Process runs are costly and take time. one kilogram of drug substance. We can
Lab experiments cost very little, pilot runs develop a new concept “from scratch”,
cost perhaps 1000 times more, and full-scale or we can refine the “current best”
manufacturing campaigns require large concept.
investments in equipment, materials and
DELIVERING VALUE TO THE PROCESS DEVELOPMENT ORGANIZATION THROUGH
WORKFLOW INTEGRATION
by Peter A. Clark
• Prepare – convert the process concept purpose tools (such as Microsoft
into a physical system that is ready to Excel and Word) are used to conduct
run. This includes scaling the process up specialized work
to meet the demand, choosing a site,
designing a new plant or selecting • Effort to convert among different
suitable existing equipment, building a representations and ensure
new plant or configuring existing consistency
equipment, preparing operating
procedures, writing control logic, • Rework caused by inconsistencies
training operators, procuring materials, and conversion errors
scheduling process campaigns, etc.
3.4. Many Different People and
• Run – make the drug substance, recover Departments Contribute to the
and re-use solvents, etc. Work
• Analyze Performance: Product OK? Many different people and
Process Performance OK? – The departments (functions) conduct the
analysis uses the critical performance activities described above. Process
dimensions mentioned earlier. Bad Research develops a cost-effective and
product is reworked or scrapped. reliable chemical route for the drug
Undesirable or unexpected process compound, at lab scale. API Process
performance drives the development of a Development scales the process up to pilot
new concept. scale, and operates pilot plants that produce
drug substance for all clinical trials and
Challenge: Different activities formulation trials. (In some companies, a
require different process representations, single organization makes all the material.
use different pieces of data and involve In others, the process is handed from
different types of analysis and data department to department, often at different
manipulation. locations, as the scale increases. Another
split, seen in some companies, is to divide
Impact on Quality Pilot Plant Operations into a separate
organization.) If the drug looks promising
• Disjoint process descriptions can in Phase II trials, Process Engineering scales
lead to inconsistent process the process up to manufacturing scale,
specifications, equipment chooses a site, and selects or designs the
specifications, etc. – if the different equipment. Project Engineering manages
descriptions are not rationalized capital projects, timelines, and oversees the
carefully work of E&C firms. Environmental and
Safety groups ensure that the process meets
Impact on Costs regulations and company standards.
Technical Operations ensures a smooth
• Effort spent building a solution from transfer of process technology from R&D to
scratch each time, because general the site, and develops the manufacturing
DELIVERING VALUE TO THE PROCESS DEVELOPMENT ORGANIZATION THROUGH
WORKFLOW INTEGRATION
by Peter A. Clark
instructions. All functions from R&D • Best practices are not defined, or not
through Manufacturing contribute to followed. Individual preferences
demonstration and early production runs at prevail.
the site.
• Different people use different
This is a greatly simplified languages in a global enterprise.
description. Many of the information flows
are actually two-way collaborations, and • People keep implicit process concepts
many activities overlap in time. Also, we in their heads. Assumptions are not
have omitted some important functions from documented and explored.
our description, such as coordinating the
clinical studies, marketing, materials Impact on Quality
management, procurement, and others.
• Interpretation errors at hand-offs
Challenge: Islands of data – isolated
repositories for data (computer and paper • Miss an alternative or fail to identify
files, scattered across individual people the consequences of bad assumptions
and departments) that are not searched
easily Impact on Costs
Impact on Quality • Translation work and
“communications iterations” at hand-
• Miss available data and make bad offs
assumptions
• Rework resulting from bad
• Use incorrect data assumptions.
• Transcription errors during manual Challenge: Sequential decision
data entry making and the resulting rework loops –
the work is passed from one group to the
Impact on Costs next, to draw on the appropriate
expertise.
• Effort to retrieve data, convert units
of measure, move data from one tool Impact on Costs
to another
• Rework when a need for change is
• Rework caused by using bad data, identified “downstream” of the
and catching the problem later decision maker
Challenge: Different people use Impact on Productivity
inconsistent or incomplete process
descriptions, because • Timelines slip
DELIVERING VALUE TO THE PROCESS DEVELOPMENT ORGANIZATION THROUGH
WORKFLOW INTEGRATION
by Peter A. Clark
3.5. Regulatory Scrutiny Increases Impact on Productivity
Complexity and Demands More
Resources • Creation and approval process slows
down material and information flows
Although every pharmaceutical
company wants their process development Challenge: Change Control –
environment to be a “hotbed” of innovation, Regulations require that all changes in
the FDA, EPA and OSHA impose complex the process be evaluated for their impact
and universal regulations that impede on product quality, the environment and
innovation. Thus, additional resources are personnel safety.
needed to ensure regulatory compliance, so
that development timelines can be Impact on Costs
maintained. These resources are generally
in the form of additional manpower to • Effort to review and approve
handle regulatory requirements and capital changes
investments to automate and document
processes Impact on Productivity
Challenge: Increased • Timing is extended as evaluation of
Documentation – regulations require each change is scrutinized
specific information on each batch made,
Challenge: Moving Target –
including manufacturing records,
Regulations are constantly changing,
personnel training records, equipment
requiring companies to continually
specifications and history, emissions
revamp their work processes and
summaries and hazard analysis.
deployed technology to meet new
Impact on Quality standards (e.g. 21CFR11 – electronic
records and signatures, Pharma MACT –
• The intent is to ensure that only high emission calculations).
quality product is moved through the
supply chain Impact on Costs
Impact on Costs • Effort to review, respond, interpret
and implement new regulations
• Effort to create, approve and store
documents. • Capital to update hardware and
software to meet new requirements
• Capital costs for document
generation (automation), storage Impact on Productivity
(paper / electronic)
DELIVERING VALUE TO THE PROCESS DEVELOPMENT ORGANIZATION THROUGH
WORKFLOW INTEGRATION
by Peter A. Clark
• Changing requirements can impact powerful software tools, integrated around a
timelines and workflows shared repository for documents, objects and
data, and supported by a solid foundation of
IT services.
4. Proposal to Address These
Challenges Tools – a broad array of powerful
decision support and productivity tools,
We propose to change the workflow to tailored to facilitate the different types of
address these challenges by exploiting a analysis and streamline the data handling
carefully designed suite of software needed for the chosen work processes. This
technology. We will first describe the includes chemical route selection, design of
software enablers, then discuss how we can experiments, data collection and analysis,
use them to improve the workflow. equipment design, production planning and
scheduling, process modeling and
4.1. Enabling Software Technology simulation, materials management, writing
operating instructions, etc. The “computing
We propose the software environment
engines” in the tools should include expert
shown in Figure 2, based on the three-tiered
systems technology to deploy “rules of
Microsoft Windows Distributed interNet
thumb” for process scale-up and equipment
Architecture (DNA). Our proposed
design, check that equipment contents are
environment contains a collection of
Presentation
Layer GUI
T
Communication - Distributed, Web-Based O
Business O
Logic Object system L
Layer
S
Communication - Distributed
Data
Layer Document Process
Process Data Lab Data Management Models
MS Repository
REPOSITORY
Figure 2. Proposed Architecture
DELIVERING VALUE TO THE PROCESS DEVELOPMENT ORGANIZATION THROUGH
WORKFLOW INTEGRATION
by Peter A. Clark
compatible with materials of construction, Data Layer – server-based documents,
examine reactive chemistry issues for files and common data. The repository must
mixtures, use heuristics to develop good provide interfaces to document management
schedules, etc. systems (e.g. Documentum) and ERP
systems (e.g. SAP), as well as data on the
Presentation Layer – a client-based physical properties of materials, equipment
GUI to launch the applications and display specifications, process descriptions, models,
appropriate views of the required data. The expert systems “rules”, experimental data,
GUI must be configurable to match the work historical and real-time process data, etc.
processes. It should support web browsers,
and be able to run in them. The GUI must IT Services – communication
be “regionalized” according to the user’s mechanisms (based on XML, HTTP and
natural language (English, French, Spanish, COM) to exchange data among the parts of
German, Japanese, etc.). the system, security mechanisms to control
access to the system, data management
The Repository can be distributed over mechanisms that allow check-in, check-out
different databases residing on multiple and version control for the repository; and
devices. It is divided into two layers to system administration tools.
simplify applications development, data
access and data management: 4.2. Workflow Improvements
Business Logic Layer – server-based How can this environment address the
objects tailored to support the work challenges identified earlier?
processes. The tools communicate with the
objects to facilitate the work. The objects Consistent, shared data eliminates
provide the different representations needed errors and rework – The shared repository
for different types of work, while ensuring for common data (materials properties,
consistency in the underlying data and equipment specifications, process runs,
process descriptions. The object model experimental results, etc.) ensures that
must be rich enough to represent the full proper information is used and eliminates
range of data manipulated during the work transcription effort and rework.
(e.g. production schedules, equipment items,
plant data, process descriptions, process Complete and consistent process
models, etc.). The objects must allow descriptions streamline communications –
concurrent access. The objects must be fully A rich, common object model ensures that
configurable to match changing business all relevant information is captured.
needs. The objects’ methods should also Regionalized GUIs and careful choices of
include expert systems technology, to the object attributes facilitate automatic
provide the capabilities mentioned above. language translation. Conversion and
The objects should facilitate automatic translation errors and the associated effort
conversion among different languages and are eliminated. Alternative views of the
different units of measure. same object accommodate individual
preferences and facilitate different tasks.
DELIVERING VALUE TO THE PROCESS DEVELOPMENT ORGANIZATION THROUGH
WORKFLOW INTEGRATION
by Peter A. Clark
Collaboration and concurrent and painlessly. Managing change is hard
efforts replace isolated, sequential work. Conner [4] offers several important
decision making – Different representations insights:
(views) of a common underlying process
description, concurrent data access, and • Understand that change is expensive.
appropriate security and change
management features allow the different • Prioritize the changes based on business
contributors to work in parallel. Conflicting benefits. Carefully assess the transition
decisions are readily exposed, so they can be costs. Ensure that the costs of the status
resolved quickly. quo are far more expensive than the
costs of the change. Focus only on the
Intellectual capital is preserved and most important issues. Ensure that those
leveraged, improving the quality of the affected understand the costs of the
results – Expert systems can be used to status quo, the urgency for the change
capture and deploy best practices throughout and the desired state.
the workflow automatically. Document
management systems can be used to store • Build a network of cascading
important work and easily retrieve it. sponsorship from top to bottom of the
affected organization. Establish a
Tailored tools reduce effort and consistent structure of rewards and
facilitate rapid evaluation of options – punishments to promote the change.
Special purpose tools are designed to
streamline important tasks and provide • Sustaining a change requires both an
decision support. This eliminates the need emotional and an intellectual
to build a solution from scratch with general commitment. Assess the level of
purpose tools. Using modeling and commitment required to achieve the
simulation in concert with experiments can change. Develop a sound strategy to
reduce the number of runs needed to find the build commitment. Provide the affected
best process parameters. people with time and involvement to
build their commitment.
The flexible architecture adapts to
business needs quickly and easily – The With a clear vision, sharp focus, sound
enterprise can modify the GUI, object model plans, persistence, compassion, patience,
and mix of tools to meet changing needs. It humor and optimism – you will succeed.
is faster and easier to tailor solutions to the
specific workflow of the individual
organization. 6. Conclusions
Process development for a new drug
5. Implementation Challenges requires balancing the need to create a
commercially attractive manufacturing
We are not naïve. Simply installing process with the need to deliver clinical
our proposed technology will not transform supplies on demanding schedules. This
the drug development workflow instantly involves several different kinds of work and
DELIVERING VALUE TO THE PROCESS DEVELOPMENT ORGANIZATION THROUGH
WORKFLOW INTEGRATION
by Peter A. Clark
the efforts of many different teams. It takes 8. Note on Trademarks and Trade
many years, and most drug candidates never Names
reach the market. These characteristics of
the drug lifecycle give rise to several key All trademarks or trade names used in
challenges that adversely impact quality, this article are the property of their
costs and time to market for process respective owners.
development.
To address these challenges, we 9. References
proposed an integrated software
environment based on the three-tiered 1. Damelio, Robert, Process Mapping,
Microsoft Windows DNA model. Our Quality Resources, 1996
proposed architecture contains a suite of
2. Rummler, Geary and Alan Brache,
powerful tools, integrated around a shared
Improving Performance: How to
repository for documents, objects and data,
Manage the White Space on the
and supported by a solid foundation of IT
Organization Chart, Jossey-Bass Inc.,
services. We highlighted the potential
1990
workflow improvements promoted by this
environment. 3. Pisano, Gary, The Development Factory,
Harvard Business School Press, 1997
Although our proposed environment
offers the potential for substantial gains, it is 4. Conner, Daryl R., Managing at the
not magic. Implementing and sustaining a Speed of Change: How Resilient
new way of working is expensive. New Managers Succeed and Prosper Where
behaviors and attitudes must be encouraged, Others Fail, Villard, 1992
learned and rewarded. These changes
demand thought and attention. They take
time. With a clear vision, sharp focus, sound
plans, persistence, compassion, patience,
humor and optimism – you will succeed.
7. Acknowledgements
The author gratefully acknowledges
the thoughtful comments and insights of
Andrew McBrien and Bruce Sanchez of
Aspen Technology. The author especially
thanks William Hendricks of Aspen
Technology for providing most of the
section on regulatory issues.