American Pharmaceutical Review

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Process Analytical Technology - Changing the Validation Paradigm

Randall Schadt, Ph.D. Pfizer Global Manufacturing, Pfizer Inc. Introduction Implementation of Process Analytical Technology (PAT) for pharmaceutical manufacturing has continued to advance and enable operations that monitor, control, and analyze critical quality attributes of processes and products while manufacturing is in progress, i.e. continuous quality verification. Pharmaceutical industry and regulatory agencies such as the FDA have emphasized the benefits of using PAT in support of a risk-based approach to cGMPs that recognizes the extent of scientific knowledge supporting process validation and process control [1]. Implementation of PAT challenges the current validation paradigm to change towards supporting quality by design so that a balance is maintained between compliance and innovation. Therefore, it is necessary to define PAT validation that is appropriate, commensurate with intended use of data, and practical for a risk-based approach to cGMPs. In this article, a validation approach is described for PAT systems and methods intended for use with existing processes and products.

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Practical Validation Approach A practical validation approach for PAT applications begins with a required Validation Project Plan stating the intended use of PAT data classified as one of three levels: Development, Information Only, or Regulatory-Filed Release. Also required is a cGMP risk assessment that states the potential impact (direct, indirect, none) on product quality for the intended use of the PAT system and/or method. Intended use defined as Development involves PAT systems and methods under experimental development or associated with demonstration of PAT feasibility for a specific use. Advancing beyond development into routine use, it must be emphasized that the majority of PAT implementation should be first classified as Information Only rather than classified for Regulatory-Filed Release. Specifically, Information Only use involves PAT systems and methods implemented to gain process knowledge by measurement of process or product quality attributes. There is no intent to use the PAT information for product release when implemented as an Information Only application. Only after knowledge has

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sufficiently matured with substantial experience in an Information Only mode of operation is it appropriate to consider the use of PAT for product release or in-process release with relevant specifications and acceptance criteria. Advancing beyond Information Only use, PAT implementation classified as Regulatory-Filed Release requires prior approval of the PAT application (system, method, specifications) being used. This may be accomplished as outlined by the FDA using the following steps [1]. First, a comparability protocol [2] can be submitted to the FDA outlining PAT research, validation, and implementation strategies. Following FDA approval of this comparability protocol, one or a combination of the following regulatory pathways can be adopted for implementation. PAT can be implemented under the facility's quality system; cGMP inspections by the FDA follow. PAT can be implemented following cGMP inspection whereby the FDA's PAT Team conducts a pre-operational review of the PAT-based facility or application. A supplement (CBE, CBE-30 or PAS) can be submitted to the FDA prior to implementation, and, if necessary, the FDA's PAT Team can perform an inspection before implementation. When PAT is used either to support material, product release or for real-time, process control rather than Information Only, use of PAT methods should not initially result in deletion of a test or relaxation of acceptance criteria that are described in the approved product application [2]. Specifically, use of PAT is considered an example of alternative analytical procedures for final product release [1]. Subsequently, after sufficient experience has been gained with use of PAT, deletion of end-product quality tests may then be considered with PAT methods in place for continuous quality verification.

Validation Requirements Based on Intended Use of PAT Data All levels of PAT implementation require a Validation Project Plan with a GMP Risk Assessment for intended use of the specific PAT application and its associated data. Each PAT project (system and its associated methods) should be risk-assessed to determine the potential impact (direct, indirect, none) on product quality. The review is also required to assure compliance with requirements applicable to the defined use of the PAT system and its associated method(s). Accordingly, associated manufacturing and quality documentation may need to be revised to reflect the procedural and practice changes that need to be adopted to implement the PAT system and its associated methods. For example, use of PAT will result in the generation of an extensive amount of data regarding the manufacturing

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process. Because substantially more product and samples are being tested with PAT methods than with traditional methods, i.e. continuous analysis vs. the traditional evaluation of a small sample set, results are more likely to be generated that make it appear that out-of-specification material or product is being made, when in fact one is seeing normal variability within the process. Specifications and procedures must be in place that account for such results, so that repetitive out-of-specification investigations are not required. Furthermore, use of ASTM standards or other internationally recognized standard practices [1] intended for PAT applications, including those contained in pharmacopoeias, may be applied. However, to do so, their use must be justified and demonstrated to be directly applicable to the intended use of the PAT system and its associated methods as defined in the Validation Project Plan. With respect to PAT system qualification, the GAMP V-Model for validation can be followed [3]. However, the GAMP V-Model must be interpreted so that PAT system qualification is appropriate and based on intended use. The need for specific system qualification documents should be justified in the Validation Project Plan. Consideration should be given to the fact that full performance qualification of a PAT system is not necessarily possible prior to conducting PAT method validation and establishing associated method specifications, e.g. using on-line PAT systems for process control. Traditionally, analytical methods must be validated according to pre-defined acceptance criteria specific to the intended use of the method with a qualified system. Analytical test method specifications, for release or not, must be consistent with the validated method. For PAT method validation, sufficient data must be acquired with a qualified system in routine operation including the process or product interface. Certainly, PAT method specifications, e.g. alert levels, action levels, release limits, should be established upon sufficient data acquired using the PAT system and method in operation. While three lots are traditionally used for process validation, this may be statistically insufficient to establish acceptance criteria for the process or product quality attribute that would be monitored or controlled by the PAT method in use. Therefore, a statistically relevant and representative sampling plan and rationale suitable for PAT method validation should be implemented, and this should account for the process or product variability that is intended to be tested, monitored, or controlled. Prior to use of PAT systems and methods for Information Only or Regulatory-Filed Release, change control practices must be implemented to maintain compliance. Periodic review of PAT systems and methods in use should identify trends in results that require preventive or corrective actions, as well as analyzing the cumulative effect of changes relative to original specifications. Periodic review should assess the validity of the PAT method consistent

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with current use of the PAT system, recommend additional system qualification testing or method validation if necessary, and determine whether PAT systems and methods should be retired, replaced, or modified. In addition to requirements discussed above, based on the intended use of PAT data, i.e. Development, Information Only, or Regulatory-Filed Release, the following requirements for PAT validation should also apply.

Development Process or Product Quality Attributes acceptance criteria not required as focus is on feasibility of PAT system or method prior to its potential use with Information Only or Regulatory-Filed Release implementation System Qualification User Requirement Specification (URS), and either Factory Acceptance Test (FAT) / Site Acceptance Test (SAT) or Vendor Installation Qualification (IQ) / Operational Qualification (OQ) tests; Vendor Audit recommended to identify vendor's compliance capabilities Method Validation - not possible due to exploratory phase of implementation

Information Only Process or Product Quality Attributes acceptance criteria under development; attributes monitored and assessed in support of gaining process knowledge or to identify opportunities to improve process or product quality System Qualification URS, Functional Design Specification (FDS), and either FAT/SAT or Vendor IQ/OQ tests; applicable pharmacopoeia tests if scientifically justified; approved IQ/OQ tests only for data functions that are used (data acquisition, data processing, data management); approved Performance Qualification (PQ) tests executed on-line or at-line (dependent on intended use) with sample matrix and including system to sample or process interface; Vendor Audit with vendor approved accordingly; Traceability Matrix that identifies the connectivity between URS, FDS, and executed qualification tests; 21CFRPart 11 assessment with any gaps identified and addressed accordingly Method Validation follows scientific strategy based on the technology and application; based on statistically relevant sampling or measurement plan including design of experiments and multivariate chemometrics when appropriate; uses qualitative acceptance criteria based on data trending, e.g. statistical process control concepts applied to develop acceptable process signature with associated quality attributes

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Regulatory-Filed Release Process or Product Quality Attributes acceptance criteria established and defined for regulatory approval; attributes monitored or controlled with acceptance criteria to support in-process release of material or to support product release System Qualification includes Information Only requirements above; approved IQ, OQ, and PQ may be more comprehensive in content of verification based on intended use of system; use and reference to integrated system testing by audited vendor may support commensurate reduction in approved IQ, OQ, and PQ testing Method Validation includes Information Only requirements above, however it differs from Information Only requirements in that a combination of qualitative and quantitative acceptance criteria may be used to support release of material or product; demonstration of equivalency to previous regulatory-filed methods is required only if scientifically justified and appropriate, i.e. some PAT methods cannot be directly correlated to traditional, lab-based methods.

Conclusions PAT implementation is facilitated by adopting a practical validation approach as described herein for PAT systems and methods based on intended use of the PAT data. The pharmaceutical industry should critically review its validation practices to enable effective use of PAT. While traditional validation experiences may have served industry's needs prior to the introduction of PAT, validation practices must now be interpreted to conform to a science-based approach that supports quality by design.

References 1. U.S. FDA, Draft Guidance for Industry, PAT A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance, August 2003. 2. U.S. FDA, Draft Guidance for Industry, Comparability Protocols Chemistry, Manufacturing, and Controls Information, February 2003. 3. ISPE (GAMP Forum), GAMP Guide for Validation of Automated Systems, GAMP4, 2001. Dr. Schadt is currently the Manager/Team Leader of Pfizer Inc., Pfizer Global Manufacturing, PAT Validation and Documentation. His responsibilities include PAT validation

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strategies and associated compliance documentation that supports PAT implementation at Pfizer sites worldwide. His ten years of pharmaceutical industry experience in quality operations and manufacturing include definition of policies, procedures, analytical methods, standards, and practical guidance for PAT validation and compliance.
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