Process validation strategy and implementation of GMP Annex 15 and FDA guidance. Continuous Process Verification (CPV).

Continuous Process Verification (CPV) is a subject that raises questions and starts with definitions. The GIC A3P CPV working group looked into the matter so that this article could clarify the terms that are different between the FDA, GMP, and European directives, and to share the actions undertaken by the group on this theme.

1. Requirements and regulatory expectations
1.1 The texts of the ICH
ICH Q8, Q9 and Q10 define a new approach to quality in pharmaceutical production. This approach is based on in-depth scientific knowledge and risk management, as well as an appropriate quality management system.
The integration of ICH concepts into the EMEA and FDA validation guides has resulted in a new approach to process validation in the pharmaceutical industry.

Traditional industrial validation usually applied to 3 consecutive batches on an industrial scale, and then to periodic revalidation batches. The new European and American directives reinforce the fact that the validation of a process is not a temporal event in the development of the product but rather a validation that lasts throughout the life of the product. The life cycle of the drug includes different stages: design and development, manufacturing on an industrial scale, marketing until it stops.
The studies carried out during the development of the process must make it possible to provide the scientific knowledge necessary to validate the process (ICH Q8 and Annex 15 GMP).
The in-depth scientific knowledge acquired during the various stages of development will allow to deepen the knowledge of the manufacturing process and thus identify the sources of variability impacting the quality attributes of the finished product and better define the control strategy.

ICH Q8 specifies the type of information needed in record folders to demonstrate knowledge of the factors that impact product quality. This directive has also introduced the notion of Quality by Design (QbD) and is thus moving towards approaches to the validation of processes based on scientific and risk management aspects. The latter is well detailed in the ICH Q9.

The ICH Q10 describes a global model of an efficient pharmaceutical quality system, based on the quality concepts of the International Organization for Standardization (ISO) and includes the GMP regulatory requirements. This guideline also complements the ICH Q8 "Pharmaceutical Development" and the ICH Q9 "Quality Risk Management". The ICH Q10 is a model of pharmaceutical quality system implemented throughout the different stages of the life cycle of a product. Part of this guideline specifically guides in the continuous improvement of process performance and product quality. This directive focuses on maintaining the state of process control and continuous process improvement by developing effective control and monitoring systems for process performance and product quality. This recommendation is an integral part of the 3 process validation step well detailed in the FDA directive. This process monitoring approach during the production of products in the marketing phase, integrating trend analysis as well as corrective and preventive actions (CAPA system), reinforces the scientific knowledge of the process acquired during development.
Adherence to the content of the ICH Q10 guideline should facilitate continuous improvement and thus strengthen the link between pharmaceutical and manufacturing development activities. Therefore, research, development, technology transfer, validation department, and industry department must communicate and work together to ensure continuity of information from each stage of the product life cycle.

This step is based on the continuous verification of the process throughout the product life cycle to support the product validation status as documented in the product quality review, incorporating process trend assessment (Appendix 15). GMP).

1.2 EMEA and FDA expectations
As a first step, a clarification of the terms presented in the FDA, GMP and European regulations is presented below.

"Continous process verification" is an alternative approach for process validation in which process performance is monitored and evaluated continuously during manufacturing. This continuous evaluation corresponds to PAT: process analytical technology (ICHQ 8).
"Continued Process Verification" corresponds to the 3 process validation step described in the FDA guidelines (Guidance for Industry Process Validation: General Principles) and also at the stage On Going Process Verification described in the European directives.

2. Considerations and issues encountered in deploying these new guidelines
2.1 The CPV approach for marketed products (legacy product) & new products
The CPV approach is applicable to all products whether they are marketed products or new products. Nevertheless, a distinction exists. The commercialized products have an old process validation and do not have all the development data that lists Critical Quality Attributes (CQA) and Critical Process Parameters (PPC). For commercialized products, it is necessary to document through a risk analysis the CQA and PPC to justify the control strategy, which is an integral part of the CPV approach.

For new products, the development is in line with current guidelines. Thus, the traditional validation phase 2.2, also called performance qualification of the process is followed by the 3A phase of setting up the continuous verification of the process on a number of predefined batches in a protocol. 4 During the 3A phase, the validation data generated will be analyzed statistically to confirm the performance and robustness of the process. The validation status of the process is confirmed at the end of the 3A phase in a documentary manner.
The 3B phase "Continuous monitoring program" follows the 3A phase according to a program and documentation to be defined. The data tracked at periodic frequency make it possible to identify the drifts of the process, to warn about the risk of out-of-specification results, which makes it possible to be proactive in the implementation of actions (CAPA system). The data collected in phase 3B can serve as supportive data for the periodic review to decide on the maintenance of the validated state.

2.2 The CPV approach and data collection, in line with expectations data integrity
The collection of data used in the context of the CPV is a real challenge, because it can be centralized or manual, and collection methods often depend on equipment, workshops and sites.
These data are critical because they document the maintenance of the validated state of the manufacturing processes. It is therefore essential to ensure compliance with the ALCOA rules set out in the FDA's December 2008 Data Protection and Compliance Guidance for FMP, Questions and Answers, Guidance for Industry. The complete, consistent and accurate data must be attributable, legible, recorded in real time, original or a true and exact copy.
These regulatory requirements can be verified through a documented and validated data collection process, whether manual or automated. However, a cost / benefit risk analysis can be done to justify or not the implementation of an automatic data collection system.

2.3 The CPV approach and integration into the pharmaceutical quality system
The implementation of continuous process verification corresponds to a profound change in the notion of traditional validation. The CPV approach is a tool for continuous improvement of quality, which must be integrated into the existing pharmaceutical quality system. The existing quality system may have to adapt to integrate the continuous collection and monitoring of data.

CPV does not replace or replace existing processes. It is a complementary tool for monitoring the control of product quality and the manufacturing process. Annual product reviews, change management processes, deviation management and corrective and preventive action systems are parallel processes to the CPV.

CPV deliverables, namely risk analyzes and trend analyzes, most often presented in protocols and reports, can be input data, or Annexes to annual product reviews. A mature CPV process can document the impact of one or more changes on the manufacturing process. The effectiveness of a CAPA can also be documented by the CPV. The quality system must be adapted for the management of non-trend results. Two processes can coexist: the out-of-specification results management process, and the off-trend results management process. The appearance of a non-trend result must be investigated, before the appearance of a result outside the acceptance criterion. It is a tool for continuous improvement.

A survey organized by the GIC A3P CPV working group concerning the implementation of CPV is currently in progress.
The first answers indicate that the process is in place for a third of the pharmaceutical companies, being deployed for a third, and in reflection for the last third. For most companies, data collection is not centralized. The industry challenge remains the collection and integrity of the data used in the context of the CPV. The CPV is a complementary tool to document the maintenance of the validated state of the manufacturing processes, through the annual product review, or a specific annual review.
You can already answer to complete this inquiry concerning the deployment of the CPV on the A3P website. https://a3p.org/gic-groupes-interet-commun/

The group is also working on the drafting of a guide taking into account the constraints of the different types of pharmaceutical industries that will be available soon.

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SCHUHLER

Estelle SCHUHLER – LFB

Estelle Schuhler, currently in charge of validation activities, followed by projects, continuous process verification at LFB Biomedicines. A member of the A3P Continuous Process Verification Working Group, she worked in a hospital setting before specializing in the field of Injectable Biomedicine.

schuhlere@lfb.fr

Moreau

Marinette MOREAU – VETOQUINOL

Marinette Moreau, Pharmacist by training and PhD in Pharmacotechnology and Biopharmacy. Galenic development manager at Vetoquinol: formulation, process validation. Within the framework of the Group's strategy, assures the role of expert for the technical evaluation of formulations or manufacturing processes, as part of the pharmaceutical product development.

marinette.moreau@vetoquinol.com

Heron

Valérie HÉRON – SANOFI

Expertise in the production of sterile injectables in the area of ​​validation / qualification and in process and technology (trouble shooting, periodic annual review, CPV, project management).

valerie.heron@sanofi.com

References

CPV : Continued process verification
OPV : On going process verification
PAT : Process Analytical Technology
BPF : Good Manufacturing Practices
FDA: Food and Drug Administration
ICH: International Council on Harmonization
EMEA: European Medicines Agency
CAPA: Corrective and Preventive Actions
CQA:Critical Quality Attribute
CPP / PPC: Critical Process Parameters / Critical Processes Parameters
CMA : Critical Material Attribute
QI : Initial Qualification
QO : Operational Qualification
QP : Performance Qualification
ALCOA expectations : Attributable, Legible, Contemporary, Original, Accurate / Attributable, Readable, Contemporary, Original, Exact
OOS : Out of specification / Out of specification
OOT : Out of Trend / Out of Trend

Bibliography

[ICH Q8] - International Council on Harmonization - Pharmaceutical Development
[ICH Q9] - International Council on Harmonization - Quality Risk Management
[ICH Q10] - International Council on Harmonization - Pharmaceutical Quality System
EU Guidelines for GMP for Medical Products - Annex 15: Qualification & Validation; March, 2015
US FDA, Process Validation: General Principles & Practices; Jan, 2011
US FDA, Data Integrity and Compliance With Drug CGMP, Questions and Answers, Guidance for Industry, Dec. 2018