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April 2002
Vol. 5, No. 4, pp. 23–26.
rule and regulations

Managing validation strategies

opening artA well-organized plan is crucial when getting your “seal of good practice”.

The past few years have seen a significant increase in the use of computerized systems in the biopharmaceutical industry. Computer-controlled analytical instruments operating in a regulated environment must comply with the requirements of the various good practices, such as Good Clinical Practice (GCP), Good Laboratory Practice (GLP), and Good Manufacturing Practice (GMP). The ultimate responsibility for ensuring compliance with current regulations, however, lies with the end user.

Increased levels of automation and computer-controlled analysis mean higher throughput and less room for human error by operators. Extensive validation is still required at installation and at regular intervals throughout a system’s life span, to ensure compliance with regulatory demands. Because of the high degree of automation and the complex systems used in today’s laboratory, technology and support are increasingly needed from specialized vendors. Many end users rely heavily on vendor-supplied information and test data to support their validation efforts.

Validation is a complex, time-consuming procedure involving different qualifications of equipment used in drug development and manufacturing quality control.

Therefore, it is of utmost importance that a well-organized approach to system validation projects be in place to ensure that

  • hardware and software function as intended,
  • the process executed is controlled and data is processed as intended,
  • the right level of documentation is developed,
  • an effective program is in place for qualifying selected vendors, and
  • appropriate training programs are implemented for relevant personnel.

An effective strategy is necessary to develop, verify, install, and maintain computerized systems. This creates a truly competitive advantage in a changing, global marketplace.

How much is enough?
One of the most important ways of maintaining the safety and effectiveness of a drug or pharmaceutical product is to maintain control over the processes used in its production and the instrumentation used in analysis. Validation is a necessary exercise for product approval. From a regulator’s perspective, time and money are of little or no importance. From a pharmaceutical company’s perspective, these issues are crucial.

It could be said that there is no such thing as too much validation; drug companies never receive a warning letter for carrying out too much validation. On the other hand, warning letters from the U.S. FDA concerning shortfalls resulting from insufficient validation are public information and can have a direct effect on a company’s market value. By getting things right the first time, companies decrease their projected time-to-start-up and time-to-market (TTM), which results in significant cost savings. TTM can be crucial, with the first product that is released for a particular indication often gaining most of the market share. Market domination can be extremely difficult for the competition to overcome.

TTM can be shortened by

  • planning validation projects properly,
  • choosing a vendor with knowledge of validation requirements,
  • assembling and developing the proper documentation in a shorter time frame, and
  • working with experienced and trained personnel.

Validation guarantees that an instrument is performing its task consistently according to specification and that the process delivers a safe and effective product to the market.

Several factors are essential for successful execution of validation projects and decreasing regulatory risks. To reach the level of compliance inherent with a risk profile of a drug company, it is important to stay up-to-date on regulatory requirements, terminology, and training. Warning letters can provide a valuable source of public information. Finally, it is advisable to use GMP-trained resources and make training an annual event.

A well-organized approach to system validation projects is crucial for success. A well-defined strategy should include

  • a system validation plan,
  • defined responsibilities for documentation and procedures,
  • multifunctional project teams,
  • operator input in the qualification protocols (as they have day-to-day experience of production), and
  • vendor audit procedures (to speed up the procedure for choosing a preferred vendor).

A consistent approach to overall project execution should be embodied in the highest level of the company-specific quality management system. This ensures consistency and efficiency when carrying out development and validation projects.

The system validation plan should be an overview of the entire validation operation, including its organizational structure, content, and planning. It should cover manufacturing and control equipment, with prospective validation alongside revalidation of existing equipment. In content, the summary document should be brief, concise, and clear, with references to policy documents agreed to by management.

A suitable vendor should be technically competent and commercially qualified to supply and support the proposed system. Knowledge of validation requirements and experience in providing systems for GMP applications are important selection criteria. Qualifications of selected vendors should be verified through on-site evaluations that focus on the vendor’s quality system. One purpose of a vendor audit is to determine the extent of testing that the user has to perform to provide a high degree of assurance that the system will operate in the intended manner.

Software validation
In essence, validation should provide evidence of control. Software can be supplied as “validated”, in the sense that it has been verified in-house by the vendor to conform with, and function according to, specification, with documented evidence of testing available on request. However, the U.S. FDA expects the pharmaceutical producer to take ultimate responsibility for the software and system. Installation qualification and operational qualification are still required, even if the software is verified and documented by the vendor.

Software validation is a two-phase task. In the first phase, the software is tested to ensure that code is developed properly and performs reliably, efficiently, and concisely. It is usually not realistic for the user to perform this type of structural testing of software, as testing for source code accuracy can be quite time-consuming. However, regardless of how and when the testing is performed, the user must be responsible for understanding and evaluating these tests.

Many vendors have elected to support their customers by performing this work themselves, raising the question of partiality. Therefore, it is advisable that an external, impartial consultant inspect the vendor software.

The second phase involves installation and operational qualification, which are performed at the user’s site. The installation qualification verifies that the software was installed correctly. For operational qualification, the software is tested in the specific application in which it is used. In general, regulatory authorities do not approve the software itself but inspect an application in which the software is to be used and offer an opinion.

Equipment qualification is the process of ensuring that a system is appropriate for its intended use. Systems cannot be delivered “preapproved”, because of the uniqueness of each production site environment. Even slight variations in temperature, voltage, or humidity, as well as different operators, can affect the equipment’s performance. Equipment qualification is commonly broken down into design, installation, operational, and performance qualification.

Design qualification relates to all procedures prior to installation of the system in its selected operating environment, outlining the functional and operational specifications. Installation qualification involves verifying complete arrival of the system as purchased, with a list of components, instruments, and required specifications to be checked and signed off. Essentially, the installation qualification should demonstrate that the user has purchased and installed the right equipment for the process.

Operational qualification includes procedures for testing the system in its selected environment. Tests are carried out and documented for key operational functions, including security, on a component level as well as for the whole system.

Performance qualification is documented verification that a method works for a specific system according to its routine usage. The pharmaceutical producer usually carries out this phase and ongoing performance tests to ensure that the system is maintained in a validated state.

Companies must satisfy both the U.S. FDA and management’s requirements for cost-efficient validation, production, and analysis. The validation management strategy must cover all stages of the process, from the concept phase to full-scale production. However, the validation project time frame must be decreased to accelerate start-up and TTM for product. With these considerations, it is often simpler and more cost-effective to outsource validation to the preferred vendor.

It is highly important to have a strict validation management strategy in place that addresses important issues such as the supplier, compliance with regulations, and staff training. This directly affects product development costs and quality. Outsourcing validation is a cost-effective option for achieving this.

Fredrik Sundberg is the marketing manager of drug development, quality control, and validation at Biacore International SA (Uppsala, Sweden). Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.

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