Process analytical technology (PAT) — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance
PAT FRAMEWORK
PAT to be a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.
The term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner.
The goal of PAT is to enhance understanding and control the manufacturing process, which is consistent with our current drug quality system,quality cannot be tested into products and product should be built-in or by design. can also be used to meet the regulatory requirements for validating and controlling the manufacturing process.
Quality is built into pharmaceutical products through a comprehensive understanding of:
- The intended therapeutic objectives; patient population; route of administration; and pharmacological, toxicological, and pharmacokinetic characteristics of a drug
- The chemical, physical, and bio-pharmaceutic characteristics of a drug
- Design of a product and selection of product components and packaging based on drug attributes
- The design of manufacturing processes using principles of engineering, material science,
and quality assurance to ensure acceptable and reproducible product quality and
performance throughout a product’s shelf life
Effective innovation in development, manufacturing and quality assurance would be expected to better answer questions such as the following:
- What are the mechanisms of degradation, drug release, and absorption?
- What are the effects of product components on quality?
- What sources of variability are critical?
- How does the process manage variability?
PAT framework is to design and develop well understood processes that will consistently ensure a predefined quality at the end of the manufacturing process. Gains in quality, safety and efficiency will vary depending on the process and the product, and are likely to come from:
- Reducing production cycle times by using on-, in-, and/or at-line 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
For example, use of dedicated small-scale equipment (to eliminate certain scale up issues)
A. Process Understanding
A 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 over the design space established for materials
used, process parameters, manufacturing, environmental, and other conditions.
In the absence of process knowledge, when proposing a new process analyzer, the test-to-test comparison between an online process analyzer and a conventional test method on collected samples may be the only available validation option. In some cases, this approach may be too burdensome and may discourage the use of some new technologies.
Transfer of laboratory methods to on-, in-, or at-line methods may not necessarily be PAT.
Existing regulatory guidance documents and compendial approaches on analytical method validation should be considered.
Process understanding then continues in the production phase when other variables (e.g., environmental and supplier changes) may possibly be encountered. Therefore, continuous learning over the life cycle of a product is important.
B. Principles and Tools
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.
To establishing effective processes for managing physical attributes of raw and in-process materials requires a fundamental understanding of attributes that are critical to product quality. Such attributes (e.g., particle size and shape variations within a sample) of raw and in-process materials may pose a significant challenge because of their complexities and difficulties related to collecting representative samples.
Formulation design strategies exist that provide robust processes that are not adversely affected by minor differences in physical attributes of raw materials. Because these strategies are not generalized and are often based on the experience of a particular formulator, the quality of these formulations can be evaluated only by testing samples of in-process materials and end products.
1. PAT Tools
Many tools available that enable process understanding for scientific, risk-managed pharmaceutical development, manufacture, and quality assurance. These tools, when used within a system, can provide effective and efficient means for acquiring information to facilitate process understanding, continuous improvement, and development of risk-mitigation strategies.
In the PAT framework, these tools can be categorized according to the following:
- Multivariate tools for design, data acquisition and analysis
- Process analyzers
- Process control tools
- Continuous improvement and knowledge management tools
a. Multivariate Tools for Design, Data Acquisition and Analysis
From a physical, chemical, or biological perspective, pharmaceutical products and processes are complex multi-factorial systems.
The development strategies can be used to identify optimal formulations and processes.
This knowledge base can help to support and justify flexible regulatory paths for nnovation in manufacturing and postapproval changes. A knowledge base can be of most benefit when it consists of scientific understanding of the relevant multi-factorial relationships (e.g., between formulation, process, and quality attributes), as well as a
means to evaluate the applicability of this knowledge in different scenarios (i.e.,generalization).
These tool can also support the development of process simulation models, which can contribute to continuous learning and help to reduce overall development time.
When used appropriately, these tools enable the identification and evaluation of product and process variables that may be critical to product quality and performance. The tools may also identify potential failure modes and mechanisms and quantify their effects on product quality.
b. Process Analyzers
Process Analyzer tools have evolved from those that predominantly take univariate process measurements, such as pH, temperature, and pressure, to those that measure biological, chemical, and physical attributes. Indeed some process analyzers provide nondestructive measurements that contain information related to biological, physical, and
chemical attributes of the materials being processed.
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
Process analyzers typically generate large volumes of data.
Certain data are likely to be 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 intra batch) showing measurement results. Ease of secure access to these data
is important for real time manufacturing control and quality assurance. Installed information technology systems should accommodate such functions.
The ability to measure relative differences in materials before (e.g.,within a lot, lot-to-lot, different suppliers) and during processing will provide useful information for process control. A flexible process may be designed to manage variability of the materials being processed.
Such an approach can be established and justified when differences in quality attributes and other process information are used to control (e.g.,feed-forward and/or feed-back) the process.
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. Robust design, reliability, and ease of operation are important considerations.
Installation of process analyzers on existing process equipment in production should be done after risk analysis to ensure this installation does not adversely affect process or product quality.
We recommend that manufacturers developing a PAT process consider a scientific, risk-based approach relevant to the intended use of an analyzer for a specific process and its utility for understanding and controlling the process.
c. Process Control Tools
To emphasize that a strong link between product design and process development is essential to ensure effective control of all critical quality attributes.
Process monitoring and control strategies are intended to monitor the state of a process and actively manipulate it to maintain a desired state. Strategies should accommodate the attributes of input materials, the ability and reliability of process analyzers to measure critical attributes, and the achievement of process end points to ensure consistent quality of the output materials and the final product.
Design and optimization of drug formulations and manufacturing processes within the PAT framework can include the following steps (the sequence of steps can vary):
- Identify and measure critical material and process attributes relating to product quality 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 process controls that provide adjustments to ensure control of all critical attributes
- Develop mathematical relationships between product quality attributes and measurements of critical material and process attributes
- Within the PAT framework, a process end point is not a fixed time; rather it is the
achievement of the desired material attribute.
Where PAT spans the entire manufacturing process, the fraction of in-process materials and final product evaluated during production could be substantially greater than what is currently achieved using laboratory testing.
Thus, an opportunity to use more rigorous statistical principles for a quality decision is provided. Rigorous statistical principles should be used for defining acceptance criteria for end point attributes that consider measurement and sampling strategies.
Multivariate Statistical Process Control can be feasible and valuable to realizing the full benefit of real time measurements. Quality decisions should be based on process understanding and the prediction and control of
relevant process/product attributes.
In a PAT framework, validation can be demonstrated through continuous quality assurance where a process is continually monitored, evaluated, and adjusted using validated in-process measurements, tests, controls, and
process end points.
Risk-based approaches are suggested for validating PAT software systems.
d. Continuous Improvement and Knowledge Management
Continuous learning through data collection and analysis over the life cycle of a product is important. These data can contribute to justifying proposals for postapproval changes.
Approaches and information technology systems that support knowledge acquisition from such databases are valuable for the manufacturers Opportunities need to be identified to improve the usefulness of available relevant
product and process knowledge during regulatory decision making.
A knowledge base can be of most benefit when it consists of scientific understanding of the relevant multifactorial
relationships (e.g., between formulation, process, and quality attributes) as well as a means to evaluate the applicability of this knowledge in different scenarios (i.e.,generalization).
2. Risk-Based Approach
In established quality system for a particular manufacturing process, we can expect an inverse relationship between the level of process understanding and the risk of producing a poor quality product.
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).
Thus, a focus on process understanding can facilitate risk-based regulatory decisions and innovation.
3. Integrated Systems Approach
The fast pace of innovation in today’s information age necessitates integrated systems for evaluating and timely application of efficient tools and systems that satisfy the needs of patients and the industry.
Many of the advances that have occurred, and are anticipated to occur,are bringing the development, manufacturing, quality assurance, and information/knowledge management functions so closely together that these four areas should be coordinated in an integrated manner.
Therefore, upper management support for these initiatives is critical for successful implementation.
The Agency recognizes the importance of having an integrated systems approach to the
regulation of PAT.
Therefore, the Agency developed a new regulatory strategy that includes a PAT team approach to joint training, certification, CMC review, and CGMP inspections.
4. Real Time Release
Real time release is the ability to evaluate and ensure the acceptable quality of in-process and/or
final product based on process data.
Typically, the PAT component of real time release includes a valid combination of assessed material attributes and process controls. Material attributes can be assessed using direct and/or indirect process analytical methods.
The combined process measurements and other test data gathered during the manufacturing process can serve as the basis for real time release of the final product and would demonstrate that each batch conforms to established regulatory quality attributes.
We consider real time release to be comparable to alternative analytical procedures for final product release.
In real time release, material attributes as well as process parameters are measured and controlled.
The Agency’s approval should be obtained prior to implementing real time release for products
that are the subject of market applications or licenses.
Process understanding, control strategies, plus on-, in-, or at-line measurement of critical attributes that relate to product quality provides a scientific risk-based approach to justify how real time quality assurance is at least equivalent to, or better than, laboratory-based testing on collected samples.
With real time quality assurance, the desired quality attributes are ensured through continuous assessment during manufacture. Data from production batches can serve to validate the process and reflect the total system design concept, essentially supporting validation with each manufacturing batch.
C. Strategy for Implementation
The Agency understands that to enable successful implementation of PAT, flexibility,coordination, and communication with manufacturers is critical. The Agency believes that current regulations are sufficiently broad to accommodate these strategies.
The Agency encourages such proposals and has developed a regulatory strategy to consider such proposals. 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
PAT principles and tools should be introduced during the development phase. The
advantage of using these principles and tools during development is to create opportunities to
improve the mechanistic basis for establishing regulatory specifications.
To use the PAT framework to develop and discuss approaches for establishing mechanistic-based regulatory specifications for their products.
During implementing the PAT framework, manufacturers may want to evaluate the suitability of a PAT tool on experimental and/or production equipment and processes.
For example,
when evaluating experimental on- or in-line process analyzers during production, it is recommended that risk analysis of the impact on product quality be conducted before installation. This can be accomplished within the facility’s quality system without prior notification to the Agency. Data collected using an experimental tool should be considered research data. If research is conducted in a production facility, it should be under the facility’s
own quality system.
Manufacturers should scientifically evaluate these data to determine how or if such trends affect quality and implementation of PAT tools.
FDA does not intend to inspect research data collected on an existing product for the purpose of evaluating the suitability of an experimental process analyzer or other PAT tool.
FDA’s routine inspection of a firm’s manufacturing process that incorporates a PAT tool for research purposes will be based on current regulatory standards (e.g., test results from currently approved or acceptable regulatory methods).
V. 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
(1) improve the scientific basis for establishing regulatory specifications,
(2) promote continuous improvement, and
(3) improve manufacturing while maintaining or improving the current level of product quality.
To be able to do this, manufacturers should communicate relevant scientific knowledge to the Agency and resolve
related technical issues in a timely manner.
In general, PAT implementation plans should be risk based. We are proposing the following possible implementation plans, where appropriate:
- 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 (CBE, CBE-30 or PAS) 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.
- A comparability protocol can be submitted to the Agency outlining PAT research,validation and implementation strategies, and time lines. Following approval of this comparability protocol by the Agency, one or a combination of the above regulatory pathways can be adopted for implementation.
Reference: Guidance for Industry (PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing,and Quality Assurance)
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