Guidance 099 – Validation of Process Analytical Technology System Pharmaceuticals quality assurance & validation procedures GMPSOP

Validation of Process Analytical Technology System

Introduction

This document provides guidance for validation of PAT systems to assure compliance for PAT applications which can be implemented at a GMP site. The scope of this guidance includes PAT systems used in both Drug Product and Active Pharmaceutical Ingredient (API) manufacturing.

This guidance provides quality risk-based recommendations for validating PAT systems and provides examples with a flow chart to assist in performing the impact assessment and determining validation requirements. The extent of validation required for a PAT system is determined by the potential risk to quality posed by its intended use.

It is recommended that an impact assessment of each PAT system be performed. Those systems that are determined by the impact assessment to have a potential impact on product quality are considered direct impact systems and shall be qualified. Others which are determined to be indirect or no impact are Commissioned.

Terminology

PAT Measurement System (or PAT system):

To enhance understanding of the content and recommendations in this guidance, terminology used in this document is defined below.

A measurement system can consist of several elements that generate analytical measurements which relate either to the identification, monitoring, or control of process parameters or product quality attributes. These elements may include one or more analyzers, instruments or sensors, either stand-alone or networked, including but not limited to those with software or firmware, as well as the interface of the system to the process or product being measured (sample interface), and interface of the measurement system to the process control system.

The PAT measurement system is typically comprised of some or all of the following:

Field hardware (e.g. sample loop, supply piping, nitrogen feed).
PAT instrument (e.g. NIR, HPLC, probe, fiber optics).
PAT software (e.g. computer program and configuration).
Data management (e.g. archival of results).
Distributed Control System connectivity.

Appendices 1 through 4 provide some examples of PAT systems and how their boundaries may be defined. As defined, a PAT measurement system does not include the PAT-associated analytical measurement method.

PAT Application:

A PAT application is the use of a PAT measurement system for a particular purpose, for example, in-process reaction completion measurement in the manufacture of an API. A PAT application includes PAT measurement system elements and the analytical measurement method.

Commissioning:

A planned, documented and managed approach to the start-up and delivery of systems (e.g. facilities, equipment, and software) to the end-user that results in a safe and functional environment that meets established design and user requirements.

Qualification:

A sub-set of validation that provides documentation that critical components of direct impact systems (e.g.facilities, equipment, and software) are properly designed, installed, and tested according to predefined acceptance criteria.

Direct Impact System:

A system (e.g. facilities, utilities, equipment, software) where operations, contact, data, control, alarm or failure is expected to have an effect on product quality or regulatory compliance.

Indirect Impact System:

A system (e.g. facilities, utilities, equipment, software) where operations, contact, data, control, alarm or failure is not expected to have an effect on product quality or regulatory compliance and which links or interfaces with a direct impact system.

Recommendations and Rationales

An impact assessment shall provide a risk-based approach to assess if a PAT system is direct, indirect or no impact, along with the extent of validation required for direct impact systems. Impact Assessments should be performed for all PAT systems. If more than one application is used for a given PAT system, the most conservative use should be considered when performing impact assessments.

The System Level Impact Assessment (SLIA) shall determine if the system is considered to be Direct Impact, Indirect Impact, or No Impact with respect to its potential impact on product quality. Not all direct impact systems will be validated to the same extent. Direct impact systems may be further evaluated to determine which components are critical to product quality and which are non-critical. In the absence of a Component Level Impact Assessment, all components of a direct impact system require validation. The Component Level Impact Assessment (CLIA), conducted upon completion of the SLIA, will generally drive the extent of the validation required for a direct impact system. Only critical components within a direct impact system require qualification. Non-critical components within a direct impact system are commissioned. This approach can significantly reduce the amount of validation required.

A decision flowchart that outlines the basic steps in the System and Component Level Impact process is attached as Appendix 5.

Prior to determining the validation strategy, the system boundaries must be defined. System boundaries can be documented or referenced within the SLIA. For example, a PAT system could be defined as a system by itself. Alternatively, it could be defined as a portion of a larger system (e.g. on-line HPLC PAT system for monitoring a reaction endpoint could be defined as a portion of the reactor system itself). A third option could be to include a portion of the PAT system (e.g. a product-contact probe) within the boundary of a larger system (e.g. a reactor and its components). In this case, the need to qualify or re-qualify the larger system must also be considered.

For PAT systems with fixed-installation probes, the most logical system boundary has the probe as part of the process equipment. If the probe is intended to be mobile and able to be used in multiple

pieces of equipment, then the probe would typically be within the PAT “system” boundary. How the system boundaries are defined can have a significant impact on the validation strategy and can reduce or eliminate the need for validation of some systems.

System Level Impact Assessment

1- Does the system come in direct physical contact with the product?

Answer yes, if a system component makes direct physical contact with the product (including in- process materials, or intermediates subsequent to the API starting material) and the component’s material of construction or the ability to clean the product contact surface will affect the product’s safety, quality or purity.

For example, a measurement probe that makes direct product contact.

2- Is the system used in cleaning, sanitizing or sterilizing?

Answer yes if a system is used exclusively for cleaning verification (i.e. there is no other cleaning verification test performed).

3- Does the system create or maintain a cGMP environmental or process condition required to preserve product quality? And

4- Does the system produce, monitor, evaluate, store or report data used to accept or reject product or material, or data used to support Regulatory Compliance – Practices?

Answer yes, for PAT systems that monitor critical process parameters, used to support release decisions.

Answer yes, for PAT systems that perform exclusive verification of critical quality attributes or specification used to support cGMP decisions.

Answer yes, for PAT systems used to fulfil a regulatory commitment (e.g. registered in-process test result)

Answer no, for PAT systems that are used exclusively to gain knowledge, where data are not used to support release decisions.

Answer no, when a PAT system is used for “processing forward” decisions where the decision is financial risk only and the product-quality attributes are verified by other means (e.g.: lab sample) at a later stage.

5- Does the system perform a function in the manufacturing, processing, packaging, labelling, testing, holding or distribution of a product or material, that is required to achieve a quality attribute or specification?

Answer yes, if the system controls a critical process parameter (CPP) (e.g feedback loop) or critical quality attribute (CQA). For definitions of CPPs and CQAs, refer to guidance 015. If a system is initially defined as an indirect impact system but it is known that the system will become a direct impact system (e.g. data from the PAT system replaces final product testing), the system should be qualified.

This should be done prior to using the system as a direct impact system and prior to using data from the PAT system to make the data comparison to discontinue the end product testing.

For systems that include laboratory instruments as part of the PAT system, the PAT system may first be categorized to determine if it has a direct, indirect or no impact on product quality. Direct impact PAT systems may then have their laboratory instrument system further categorized per guidance 032 which addresses qualification of laboratory equipment.

In addition to validation of the PAT system, the validation of the PAT-associated analytical test method may also be required depending on the impact assessment. Note that a PAT application that is determined to have no impact or indirect impact does not require analytical method validation, however method validation may be needed to assure reliability of the data. If a PAT system is direct impact, and the answer to questions 4 and/or 5 is “yes”, then the analytical test method should also be validated. When one direct impact PAT system is used to support multiple analytical test methods (e.g. an HPLC PAT system used to monitor reaction endpoints for multiple API processes), the PAT system should be qualified separately from the validation of the analytical test method.

Validation of analytical test methods for PAT applications is outside the scope of this guidance.

Component Level Impact Assessment

Primary considerations when determining if a system component is critical or not are listed in are listed in the following questions.

1- Does the system component control or perform a direct impact function, or provide verification that a direct impact function has acceptable performance? And

2- Does the system component produce, monitor, evaluate, store or report direct impact data?

Impact / Risk Assessment Examples

Three examples of Impact Assessments have been prepared using the same PAT system to show how then extent of validation will vary based on intended use of the data. The concept of increasing levels of Commissioning and Qualification requirements as they relate to these three examples is shown at a high level in the chart in Appendix 6. These examples provide a representation of impact assessment results, and are attached in Appendices 1, 2, and 3 and are briefly described in the table below.

Figure 1:

Example 1 (Appendix 1): Indirect Impact: A non-regulatory test conducted using PAT that is independently verified by other established quality tests. For example, an on-line PAT application may be used to determine the % of un-reacted starting material following a reaction. Once the result is within the acceptable range, the batch will be processed forward to the next vessel. Once the material is isolated, the % of un-reacted starting material is tested on a sample of the isolated material by the QC laboratory and it must conform to a specification.

In this case, there is no risk of releasing material that does not meet product quality requirements because the QC tests are being utilized to either release (if an API) or approve the material for processing in the next synthetic step. Considering the use of the data, this application would be considered an indirect impact system.

One must also consider other aspects of this system, such as whether it has direct product contact, to determine if any components would require qualification. In this example, the direct product contact surfaces of the system are qualified as part of the reactor system. The boundary for the PAT system has therefore been drawn to exclude the product contact components from the PAT system and include those components in the reactor system itself. This PAT system would require commissioning only. However, defined this way, the qualification of the reactor would need to be considered under change control for direct impact systems.

Example 2 (Appendix 2): Direct Impact: A regulatory test conducted using PAT to demonstrate compliance with either a regulatory-filed product release specification or an in-process release specification that is not verified by other established quality tests.

For example, an on-line PAT application may be used to determine the % of un-reacted starting material following a reaction. If the % of un-reacted starting material is an in process, regulatory filed specification and the test is not backed up by established quality testing at the time of the reaction completion, then this is considered a direct impact PAT application and would be required to be validated.

As with the first example, one must also consider other aspects of this system, such as whether it has direct product contact, to determine if any components would require qualification. Because this case is a direct impact system, the PAT system will be qualified. The system components in direct contact with product can be included within the scope of the PAT system and qualified as a component of the PAT system, or they can be included within the scope of the reactor system itself and qualified as part of the reactor system.

For this Direct Impact System, a Component Level Impact Assessment was performed and is attached as an example in Appendix 4

Example 3 (Appendix 3): No Impact: A PAT system that is used to measure the % of un-reacted starting material following a reaction for purposes of optimizing yield only. There is no impact on product quality if under-reaction or over-reaction takes place. The data are not used to release material and the test is not included within a regulatory filing.

As with the first example, one must also consider other aspects of this PAT system, such as whether it has direct product contact, to determine if any components would require qualification. In this example, the direct product contact surfaces of the PAT system are qualified as part of the reactor system. The boundary for the PAT system has therefore been drawn to exclude the product contact components from the PAT system, and include qualification of those components in the reactor system qualification. This PAT system would require commissioning only.

Conclusions

Quality risk-based, impact assessment of PAT systems and PAT applications is fundamental to establishing the validation strategy. By utilizing concepts presented in this GUIDANCE, validation resources can be targeted to those applications with direct impact on quality that require qualification, while still ensuring the robust operation of lower risk applications via commissioning.