Process Analytical

Technology
A framework for
Innovative Pharmaceutical Development,
Manufacturing and Quality Assurance

Background
Laboratory testing conducted to evaluate quality
Provide quality pharmaceuticals to public
Opportunities:
Product and process development
Process analysis
Process control

Embracing Innovation
PROs

CONs

Safety, Effectiveness and Affordability

Health of Consumers
Challenges of New Discoveries

Regulatory Uncertainty
Rigid Regulatory System
Other scientific and technical issues

Challenge for Regulatory Policies

Pharmaceutical CGMPs for the 21st

Century: A Risk-Based Approach
Initiated by Food and Drug Administration to ensure:
Most up-to-date concepts of risk management and quality
systems approaches in manufacturing
Use of latest scientific advances in pharmaceutical
manufacturing and technology
Submission review and inspection programs operate in
coordinated and synergistic manner

Pharmaceutical CGMPs for the 21st

Century: A Risk-Based Approach
Initiated by Food and Drug Administration to ensure:
Regulations and manufacturing standards are applied
consistently by Agency and manufacturer
Management of the Agency's Risk-Based Approach encourages
innovation in the pharmaceutical manufacturing sector
Agency resources are used effectively and efficiently to address
the most significant health risks

Pharmaceutical CGMPs for the 21st

Century: A Risk-Based Approach
Ultimate Goal
Improve the public's access to quality health care
services

Desired state of pharmaceutical

manufacturing and regulation
Product quality and performance are ensured through the
design of effective and efficient manufacturing processes
Product and process specifications are based on a
mechanistic understanding of how formulation and
process factors affect product performance
Continuous real time quality assurance

Desired state of pharmaceutical

manufacturing and regulation
Relevant regulatory policies and procedures are tailored
to accommodate the most current level of scientific
knowledge
Risk-based regulatory approaches recognize
the level of scientific understanding of how formulation and
manufacturing process factors affect product quality and
performance
the capability of process control strategies to prevent or
mitigate the risk of producing a poor quality product

Process Analytical Technology

System for designing, analyzing, and controlling
manufacturing through timely measurements of
critical quality and performance attributes of raw and
in-process materials and processes, with the goal of
ensuring final product quality
Enhance understanding and control the manufacturing
process
Quality cannot be tested into products; it should be
built-in or should be by design

Building Quality
Multi-factorial
Characteristics of a drug
Design of a product
Selection of product components
Packaging based on drug attributes
Manufacturing processes design (engineering, material
science, and quality assurance) to ensure acceptable
and reproducible quality through shelf life

Building Quality
Reducing production cycle times by using on-, in-, and/or atline measurements and controls
Preventing rejects, scrap, and re-processing
Real time release
Increasing automation to improve operator safety and
reduce human errors
Improving energy and material use and increasing capacity
Facilitating continuous processing to improve efficiency and
manage variability (use small-scale equipment to eliminate
scale-up issues)

Process Analytical Technology

Innovation and Efficiency
Pharmaceutical Development
Manufacturing
Quality Assurance
Approach in addressing anticipated technical and
regulatory issues and questions

Process Understanding
Process is generally considered well
understood when:
(1) all critical sources of variability are
identified and explained;
(2) variability is managed by the process; and
(3) product quality attributes can be
accurately and reliably predicted

Process Understanding
Focus on process understanding can reduce the burden for validating
systems by providing more options for justifying and qualifying
systems
Provide increased insight and understanding for process
development, optimization, scale-up, technology transfer, and
control.
Process understanding then continues in the production phase
where other variables (e.g., environmental and supplier changes)
may possibly be encountered.

Principles
and
Tools
Pharmaceutical manufacturing processes
often consist of a series of unit operations,
each intended to modulate certain properties
of the materials being processed.
To ensure acceptable and reproducible
modulation, consideration should be given to
the QUALITY ATTRIBUTES of incoming
materials and their process-ability for each
unit operation.

Principles and Tools

Currently, most pharmaceutical processes

are based on time-defined end points which do
not consider the effects of physical
differences in raw materials.
Appropriate use of PAT tools and principles
provide relevant information relating to
physical, chemical and biological attributes.

PAT Tools

Multivariate tools for design, data

acquisition and analysis
Process analyzers
Process control tools
Continuous improvement and
knowledge management tools
Combination or ALL: may be applicable to a single-unit operation, or
to an entire manufacturing process and its quality assurance.

Multivariate tools for design, data

acquisition and analysis

Pharmaceutica
l Products

Pharmaceutica
l Processes

Multi-factorial systems
Many development strategies can
be used to identify the optimal
formulations and processes.

Optimal formulations and

Processes
Foundation for product
and process design

Knowledge can be used to support and

justify regulatory paths for innovation in
manufacturing anf postapproval changes.

 Information from the optimization process

can be processed using multivariate
mathematical approaches:
Statistical design of expts
Response surface
methodologies
Process stimulation
Pattern recognition tools
Knowledge management
systems

Statistical evaluation of model

predictions
- To assess applicability and reliability of
information in the form of mathematical
relationships

Integrated Systems
Approach

Integrated Systems Approach

evaluating and timely application of efficient tools and
systems that satisfy the needs of patients and the
industry.

Developme
nt
Information
Managemen
t

Coordina
ted in an
Integrat
ed
Manner

Quality
Assurance

Manufacturi
ng

Integrated Systems Approach

the Agency developed a new regulatory strategy that
includes a PAT team approach to joint training,
certification, CMC review, and CGMP inspections.

Real Time Release

the ability to evaluate and ensure the acceptable quality
of in-process and/or final product based on process
data.
PAT component:

Material attributes
assessed using direct and/or indirect process analytical methods.
Process controls
serve as the basis for real time release of the final product

Strategy for Implementation

Regulations can effectively support innovation when
clear, effective, and meaningful communication exists
between the Agency and industry, for example, in the
form of meetings or informal communications.

Strategy for Implementation

The Agency's regulatory strategy includes the following:
A PAT team approach for CMC review and CGMP inspections
Joint training and certification of PAT review, inspection and
compliance staff
Scientific and technical support for the PAT review, inspection
and compliance staff
The recommendations provided in this guidance

Strategy for Implementation

PAT principles and tools should be introduced during the
development phase.
Manufacturers evaluate the suitability of a PAT tool on
experimental and/or production equipment and
processes.
Those data used to support validation or regulatory
submissions will be subject to inspection in the usual
manner.

PAT REGULATORY APPROACH

One goal of this guidance is to tailor the Agency's usual
regulatory scrutiny to meet the needs of PAT-based
innovations that:
improve the scientific basis for establishing regulatory
specifications
promote continuous improvement
improve manufacturing while maintaining or improving the
current level of product quality

PAT REGULATORY APPROACH

Close communication between the manufacturer and
the Agencys PAT review and inspection staff will be a
key component in this approach.
To facilitate adoption or approval of a PAT process,
manufacturers may request a preoperational review of a
PAT manufacturing facility and process by the PAT Team

Proposed risk based PAT

implementation plans
PAT can be implemented under the facility's own quality
system. CGMP inspections by the PAT Team or PAT
certified Investigator can precede or follow PAT
implementation.
A supplement can be submitted to the Agency prior to
implementation, and, if necessary, an inspection can be
performed by a PAT Team or PAT certified Investigator
before implementation.

Proposed risk based PAT

implementation plans
A comparability protocol can be submitted to the
Agency outlining PAT research, validation and
implementation strategies, and time lines.

Methodological
experiments
statistical principles of

based

on

Orthogonality
The orthogonality principle is most commonly used in the
setting of linear estimation

Reference distribution
Randomization
To identify and study the effect and
interaction of product and process
variables
*Traditional one-factor-at-a-time experiments do not address
interactions among product and process variables.

Mutivariate tools
Used to identify and evaluate factors which affect the
product quality and performance:
Product and process variables
Potential failure modes and mechanisms and
quantify effects on product quality

Process analyzers

Process Analyzers
tools have evolved from those that take univariate
process measurements, such as pH, temperature,
and pressure, to those that measure biological,
chemical, and physical attributes

These measurements can be:

At-line
Measurement where the sample is
removed, isolated from, and analyzed in
close proximity to the process stream
On-line
Measurement where the sample is
diverted from the manufacturing process,
and may be returned to the process
stream.
In-line
Measurement where the sample is not
removed from the process stream and
can be invasive or noninvasive

 Data from Process Analyzers are relevant

for routine quality assurance and
regulatory decisions.

In a PAT environment, batch records

should
include
scientific
and
procedural information indicative of
high process quality and product
conformance.
For example, batch records could include a series
of charts depicting acceptance ranges, confidence
intervals, and distribution plots (inter- and
intrabatch) showing measurement results

To assess the reliability of predictive mathematical

relationships,
Comprehensive statistical and risk analyses of the
process are needed.

 Critical: design and construction of

Process equipment
Analyzer
Interfaces
Design and construction of the process equipment, the
analyzer, and their interfaces are critical to ensure that
collected data are relevant and representative of
process and product attributes.

Process Control Tools

Process monitoring and control

strategies
- Intended to monitor the state of a process and actively
manipulate it to maintain a desired state
- Should accommodate:

1. Attributes of input materials

2. Ability and reliability of process analyzers to
measure critical attributes
3. Achievement of process end points to ensure
consistent quality of output materials and final
product

Design and optimization of drug formulations and manufacturing

processes within the PAT framework can include the following
steps:

Material and process

attributes

Identify and measure critical

material and process attributes
relating to product quality

Process measurement system

Design a process measurement
system to allow real time or near real
time (e.g., on-, in-, or at-line)
monitoring of all critical attributes

Design and optimization of drug formulations and manufacturing

processes within the PAT framework can include the following
steps:

Process controls
Design process controls that provide
adjustments to ensure control of all
critical attributes

Mathematical relationship

Develop mathematical relationships

between product quality attributes and
measurements of critical material and
process attributes

Process Window
- A range of acceptable process times is likely to be
achieved during the manufacturing phase and
evaluated

Considerations to address significant deviations from

acceptable process times should also be developed

 Rigorous statistical principles should be used for

defining acceptance criteria for end point attributes that
consider measurement and sampling strategies
ex. Multivariate Statistical Process Control

Process
understandin
g

Prediction
and control of
relevant
process/produ
ct attributes

Quality Decisions

Continuous improvement and

knowledge management tools
Collected and analyzed data over the life cycle of a
product can contribute to justifying proposals for
postapproval changes.

To be of value for regulatory decision

making, product and process knowledge
should be able to explain the following:

Multifactorial relationships
- ex. Between formulation, process
andquality attributes

Means to evaluate its applicability in

different situations

2. Risk-based
Approach

Risk-based Approach
Within an established quality system and for
a particular manufacturing process, one
would expect an inverse relationship
between the level of process understanding
and the risk of producing a poor quality
product.

Risk-based Approach
For processes that are well understood,
opportunities
exist
to
develop
less
restrictive
regulatory
approaches
to
manage change (e.g., no need for a
regulatory submission).

Risk-based Approach
Thus, a focus on process
understanding
can
facilitate
risk-based
regulatory decisions and
innovation.