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ASTM E2500 is a standard relating to the specification, design and verification of Pharmaceutical and Biotechnological manufacturing systems and equipment. It is applicable to equipment; systems/processes; utilities (industrial, clean); laboratory systems; I.T. and automation systems that may affect product quality and patient safety.
"ASTM E2500 is above all a state of mind, a change of culture! "
Consensus approved in May 2007, published in June 2007, then re-approved in 2012, this guide is in line with international regulatory requirements, and ICH Q8, Q9, Q10 (Quality by Design, Quality Risk Management, Pharmaceutical Quality System). Supported by the FDA, this widespread approach in the US is starting to be rolled out in Europe, especially to industrialists. eager to rationalize the test phases of their systems before going into operation and reduce their Time to Market.
ASTM E2500(1) has many similarities to the classic "V" cycle process from the definition of requirements to the maintenance of the validated state. The great novelty of this ASTM E2500 text lies in the fact that all the tests to be performed no longer follow a rigid FAT / SAT / IQ / OQ / PQ sequence as described in the 15 Annex of the EU GMP. All of these tests, collectively referred to as "Verification", can now be organized more freely and rationally in order to be more efficient and adapt to each context.
The ASTM model
The ASTM E2500(1) model is hinged around 4 steps and 4 cross-functional processes:
- 4 steps: Requirements; Specification & Design; Verification; Acceptance & Release.
- 4 cross-functional processes: Good Enginneering Practices; Quality Risk Management, Design Review, Change Management.
The ASTM E2500 model highlights new players: : Subject Matter Experts and suppliers.
The ASTM E2500 method makes it possible to control the implementation of a system in production and to secure the projects by focusing on the critical aspects from a GMP point of view, at each stage of the process.
The risk management approach focused on product quality and patient safety enables tailoring of requirements specification efforts and streamlined verifications.
Step 1: Requirements
The "requirements" are the basis of the Verification, the whole documentary pyramid relating to the verifications is built on these foundations. It is important that they are clearly defined. Input data is knowledge of the product, knowledge of the manufacturing process, regulatory requirements and internal company requirements. The implication of the users and EMS in this step is then essential, they will identify the different user needs and will facilitate the identification of the critical aspects.
Step 2: Specification & Design
This step is aimed at verifying that the needs and requirements of the various users have been taken into account by the project unit and supplier. It is an iterative step; regular meetings are held to adjust solutions proposed by suppliers and ensure they are clearly understood. Where a prototype is concerned, it is evident that the design can only be partially defined. In fact, sometimes the verification step is needed to finalize it.
Step 3: Verification
The verification phase is based on two major principles: "the right test" performed at the "right time" = "right first".
The application of these two principles allows the execution of a "right first" test. Performed too early the validity of its results may be challenged by modifications, disassembly or transport; executed too late it penalizes the planning of the project.
Moreover, the Verification process consists in limiting test duplication. Tests are only repeated if necessary or in the event of a change. Accordingly, some tests may be conducted at the supplier's site, either totally or partially. Similarly, some tests may be delegated to suppliers as they are experts in their own systems.
Step 4: Acceptance & Release
The Acceptance & Release step paves the way for the release of the system for operational implementation. During this step, it is important to draw up a summary document listing all tests carried out, the dates they were carried out and their status. The system concerned can then be transferred to the following step.
Should reservations remain at the point of transfer, they should only concern non-critical aspects and resolution dates must be defined.
Process 1: Good Engineering Practicess
Good Engineering Practices are a matter of common sense: good, well-defined and shared organization from the start of a project facilitates its implementation. Poorly defined or undefined organizational problems at the start of a project will inevitably contaminate technical problems that will certainly arise.
Process 2: Quality Risk Management
A product-focused risk analysis is carried out to identify, at the earliest possible stage, critical parameters from a quality / patient safety point of view (CQA, CPP). The quality risk management approach also makes it possible to focus on the verification of critical aspects of the system / installation of interest from a GMP point of view.
Process 3: Design Review
The design review is an iterative process. Accordingly, it has to be approached on a step by step basis as supplier design documents are published. This phase is critical to ensuring the system design meets needs. It is aimed at reducing the need for any modifications following handover of the system to end users, as well as avoiding repeat tests following a modification that can have a considerable impact on the launch of production. As above, it is evident that this process closely mirrors the Specification & Design step. Consequently, this activity should be repeated whenever there is a design change.
Process 4: Change management
It is obvious that in the ASTM E2500 approach, the change management process will start earlier. Test duplication will be avoided provided change is managed, tests that may be conducted at the supplier's site, even if only partially.
Conversely, since modifications are identified at an early stage via a well-prepared design, they should be easier to resolve as a result.
The process set out in ASTM E2500 is based on an organization whereby R&Rs are clearly defined and better use is made of various Project players' expertise :
- SMEs play a crucial role in ASTM E2500(1). Indispensable from the beginning of the project, they participate in the definition of needs, the identification of critical aspects, the system design review, the development of the verification strategy and the choice of acceptability criteria. . They also carry the approach by the Quality Risk Analysis.
- Suppliers, true SME systems, can be see, depending on their level of maturity, assigning certain verification tests; this makes it easier to reach "the right test" executed at the "right time" = "right first". In projects conducted under the ASTM E2500 approach, suppliers play a key role. They must know the principles of ASTM E2500 and be trained in regulatory requirements, especially good documentary practices.
- QA controls and focuses its efforts on critical aspects of the processes and systems that may have an impact on product quality. In particular, it validates all verification acceptance criteria related to critical aspects.
This organization is reflected in different resources being mobilized throughout the project. Such an approach makes it possible to take full advantage of the expertise of each individual player, and thus better safeguard projects.
ASTM E2500 is an approach that goes well beyond verification. It covers the entire project and involves all players from the very start of the project, from the needs definition phase. Driven by solid anticipation of the design step and the appropriate blend, the approach enables efficient verification via the execution of the right tests at the right time.
"Those who walk slowly can, if they follow the right path, go much further than those who run rapidly in the wrong direction." René Descartes
Gérôme AVENOSO - LILLY France
Gérôme Avenoso starts his nuclear career before joining Lilly in 1993 when he sets up the C & Q structure. After his intervention on several local projects, he covers the CQV activities on all corporate projects realized in Europe. He then participates in a global program consisting of 4 similar projects located in Italy, the United States, France and China, the object being to replicate to be more effective. It also includes a think tank on the C & Q method aimed at making the method simpler and faster in connection with ASTM E2500 as well as promoting the harmonization of approaches across all Lilly sites.
Jacqueline BESSET - ASSYSTEM
Maëlle DESREUMAUX - ASSYSTEM
Stephane BERTRAND - LILLY France
ASTM: American Society for Testing Material
C&Q: Commissioning & Qualification
CPP: Critical Process Parameter
CQA: Critical Quality Attribute
CQL: Commissioning Qualification Validation
FAT: Factory Acceptance Tests
GEP: Good Engineering Practices
GMP: Good Manufacturing Practices
IQ : Qualification Installation
OQ : Operational Qualification
PQ : Performance Qualification
QA : Quality Assurance
R&R: Role & Responsibility
SAT: Site Acceptance Tests
SME: Subject Matter Expert
T to Market Time to market
 ASTM E2500: Standard Guide for Specification and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment
– ISPE Guide: Science and Risk-Based Approach for Delivery of Facilities, Systems, and Equipment
– ICH Guides: (International Conference on Harmonization) EU GMP Annex 15