The Validation Process

Overview

Introduction

This chapter looks at the validation process. Note: This validation process is used to validate a specific computer system. It may be done on an existing computer system or on a new computer system.

Purpose

The purpose of the validation process is to provide a high degree of assurance that a specific process (or in this case computer system) will consistently produce a product (control information or data) which meets predetermined specifications and quality attributes.

The Validation Facets

The validation effort consists of 5 specific facets or processes, each alone, would not constitute a validation.  However, depending on the specifics of the application, system or process, would depend on which facets would be required.  There following facets are: ·  The Validation Master Plan (VMP) ·  The Project Plan ·  Installation Qualification (IQ) ·  Operational Qualification (OQ) ·  Performance or Process Qualification (PQ)

Types of validation

The two types of validation are: ·         Prospective validation: the validation of a new system as it is developed ·         Retrospective validation: the validation of an existing system

Validation process		The validation process and document references are shown below:
Step	Action
1	Establish Team(s)
2	Determine Validation Activities
3	Write the Validation Protocol
4	Specify the System Development Details
5	Perform Qualification Activities
6	Develop/Review Controls and Procedures
7	Certify the System
8	Review Periodically

Steps 1 to 8

Introduction

This topic provides an overview of the validation process.

Step 1: Establish team(s)

The first step in the validation process is to establish the System Validation Team and if required the System Validation Steering Team. These are the teams that will be responsible for the validation process.

Step 2: Determine validation activities

The second step in the validation process is to determine and record all of the validation activities that will be undertaken in order to validate the computer system. The validation activities are the exact details or activities that will be required for each of the steps in the validation process. The output from this activity will be the Validation Plan. Example: At step six of the validation process (Develop/Review Controls and Procedures) the exact controls and procedures that will be required to keep the computer system validated will be determined and recorded. Note: The type and number of validation activities will depend on the nature of the computer system that is being validated.

Step 3: Write the Validation Protocol

The third step in the validation process is to write the Validation Protocol. The Validation Protocol describes the procedure and the steps within the procedure that will be followed in order to validate the system. The Validation Protocol must also provide a high level description of the overall philosophy, intention and approach.

Step 4: Specify the system development details

The fourth step in the validation process is to specify the system development details. You should specify to the supplier or developer of a system that they must have: ·         a good methodology in order to develop a system ·         a formal quality management system for the development, supply and maintenance of the system You may need to specify to the supplier or developer the types of items you want to see - this could be done in the form of a Quality Plan. These items will help you ensure that the supplier or developer has a good methodology and formal quality management system in place. Examples: Items that will help you ensure a good methodology and formal quality management system include: ·         quality management procedures ·         life cycle definition ·         specifications, for example user requirements specification and functional specification ·         documentation controls and various items of documentation, for example user manuals and administrator documentation ·         testing procedures If the computer system is a new one, then the system development requirements will be identified prior to system selection/development. If the computer system is an existing one, then the system development requirements will still be identified and used as a basis against which to evaluate the system.

Step 5: Perform qualification activities

The fifth step of the validation process is to perform the qualification activities, which are comprised within the validation process. Some examples of these qualification activities include: ·         Supplier audit ·         Specification qualification ·         Design qualification ·         Installation qualification ·         Operational qualification ·        Performance qualification

Step 6: Develop / review controls and procedures

The sixth step of the validation process is to develop/review controls and procedures. If the computer system is a new one, then you will need to develop the controls and procedures, or check the suitability of existing generic procedures applicable to the site or department. If the computer system is an existing one, then you will need to review the controls and procedures and update them if required.

Step 7: Certify the system

The seventh step of the validation process is to certify the system. This step is where you certify that the validation deliverables have met the acceptance criteria that were described in the Validation Protocol. When you certify the system you should prepare a validation report. The validation report should outline the details of the validation process. Examples of details that should be outlined include: ·         what was done and the results that were obtained ·         any special considerations ·         whether the validation procedure (as described in the Validation Protocol) was followed ·         a summary of all documentation that was generated ·         the location of the validation documentation ·         the retention period for the documentation

Step 8: Review periodically

The eighth and final step of the validation process is to review the system validation periodically. The system should be reviewed periodically to provide additional assurance of validation. There should be documentation outlining the details of how the review is to be done and what the review should cover. The end result of a review should be a summary of the review and a recommendation as to what to do next.

Timing and Documentation

Introduction

This topic looks at the timing of the validation process and documentation.

Timing

Ideally, the validation process begins at the inception of the system selection or design process. It then proceeds alongside the system development and is completed prior to implementation of the system. Many aspects of computer systems validation are just "Good Informational Resources (IR) Practice" and as such should occur anyway during the implementation of a system. For many reasons, a system may not have been validated until after it has been in use for some time. The basic validation process is the same as for a new system. The timing of some of the validation activities may, however, differ. Note: Retrospective validation is becoming increasingly unacceptable to regulatory inspectors. New systems should be validated before use.

Timing for a new system

The steps in the validation process, and their associated validation activities are performed in parallel with the system development life cycle and reference the development documentation as it is produced.

Timing for an existing system

For existing systems, the validation activities will still follow the development life cycle but will reference the development documentation retrospectively.

Example

An example of the parallel between system development and validation activities is shown below. * Functional Specification can comprise mechanical, electrical and software functional specification for systems embedded in equipment ** Systems embedded in equipment with significant control and monitoring instrumentation *** Testing carried out by supplier can form part of subsequent qualification activities if adequately controlled. This can help reduce the amount of testing needed later, particularly at operational qualification.

 

Documentation

Every step in the validation process, and the activities within the steps, requires documented evidence that the steps or activities have been completed. The table below shows the documents that must be generated at each step. Note: In some cases some of these documents may not be required.

Step	Action	Documents Generated
1	Establish Validation Team(s)	·         Team Charter ·         Terms of Reference ·         Role Definition ·         Team Organization Chart
2	Determine Validation Activities	·         Validation Plan
3	Write the Validation Protocol	·         Validation Protocol
4	Specify the System Development Details	·         Systems Development Life Cycle documentation
5	Perform qualification activities	·         Supplier Audit Report ·         In-house Audit Report ·         Source Code Review Report ·         Specification Qualification Report ·         Design Qualification Report ·         Installation Qualification (IQ) Protocol ·         IQ Results ·         IQ Summary Report ·         Operational Qualification (OQ) Protocol ·         OQ Results ·         OQ Summary Report ·         Performance Qualification (PQ) Protocol ·         PQ Results ·         PQ Summary Report
6	Develop/Review Controls and Procedures	·         SOPs (Standard Operating Procedures) ·         Training procedures ·         Training records
7	Certify the System	·         Validation Report ·         Validation Certification
8	Review the System Validation Periodically	·         Periodic Review Procedure ·         Periodic Review Audit Report

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Outsourcing Critical Cleaning

Considerations for custom cleaning and packaging services

By Michael Lehtinen

The pharmaceutical industry is constantly reviewing strategies to improve profitability and process efficiency. Many technological advances have been — and continue to be — implemented to help facilitate this. However, outsourcing is an area, particularly in the current financial climate, that is providing value across the board, from R&D through to manufacturing. Regulatory compliance is influential in this shift; it is essential for risk prevention, yet can be time-consuming, dragging on internal resources and potentially impacting production run-time. Critical cleaning is one area that faces such challenges and is often under review.

Photo courtesy of EP Scientific, part of Thermo Fisher Scientific

Any pharma/biopharma company utilizing critical working environments needs to ensure that all equipment is fully validated and, where appropriate, certified ‘clean.’ This is the case for both the upstream R&D laboratory and the downstream manufacturing facility. In the manufacturing setting, depyrogenation and sterilization are a matter of paramount importance to production quality; maintaining a clean environment and utilizing certified clean vials and containers ensures the ultimate provision of microbiologically safe and uniform parenteral pharmaceuticals.

Beyond patient safety, remaining compliant to the stringent regulatory requirements is also of significant financial benefit to a pharma company in both the long and short term. A re-run of production due to contamination — or worse, a withdrawal of a product batch from the market — has massive cost implications in terms of time, materials, production and reputation. In order to gain assurance that the complex regulations associated with cleaning are consistently met and that containers for critical environment applications are processed and certified to exacting specifications, companies can outsource this time-consuming task.

What Does Critical Cleaning of Containers Involve?

Although sample tubes, containers and associated closures are not necessarily high value products, what they contain is. Consequently, ensuring these are as clean as the processes and environments in which they are used requires the understanding and adoption of proven methods to guarantee essential GMP quality assurance and traceability. An in-depth appreciation of the applications for which the containers will be used is, therefore, necessary to ensure that the best cleaning process is implemented, while keeping costs to a minimum. There are a variety of container-cleaning methodologies available, all designed to meet different cleaning requirements these include: surface modification, via silanization or siliconization, depyrogenation, sterilization and low particulate cleaning.

Following cleaning, every batch of containers must be tested and certified for cleaning validation purposes. There are a large number of potential analytical parameters necessary to enable certification. These will depend on the potential application of the container, but can include GC, GC/MS, ICP/MS, AA, and GF-AA, as well as other testing techniques such as those for endotoxin and sterility testing. Finally, to meet traceability requirements, all raw data and benchwork must be retained and samples from every lot tested should ideally be archived for 10 years.

Knowledge of appropriate safety and regulatory requirements is also essential, not only for current regulations, but also how they may change in the future. The pharmaceutical industry requires a wide selection of chemicals and processes to achieve better contamination control at lower costs. However, health and environmental concerns have resulted in restrictions on the use of certain chemicals and processes. To foresee future trends, an understanding of how the approaches of regulatory agencies may change over time is advantageous.

Why Outsource It?

It is evident that cleaning newly manufactured drug product containers to appropriate specifications is a costly process in terms of time, resources and in-house expertise. Consequently, this task has increasingly been outsourced during the last three to five years. Since outsourcing companies have the expertise to ensure that all containers are compliant with various regulations, such as those from the FDA and U.S. Pharmacopeia (USP), in-house expertise is no longer essential. Costs can, therefore, be saved on training and laboratory researchers are freed to focus on product development.

Furthermore, many pharmaceutical laboratories require a variety of different batch sizes depending on the stage in the process, ranging from discovery through to scale-up. For example, a new drug still in the discovery stages or clinical development may only require a few dozen containers to package the product under development. However, even though such experiments are only being performed on a small scale in the laboratory, the protocols adopted should be similar to those used in final production to ensure that results are not compromised by laboratory grade containers. As data is accumulated the number of experiments and tests increases, driving the need to a few hundred containers. However, these volumes are still very small when compared to the equipment used to process the final product. The process of loading and setting up a high speed line, which is likely to be installed in a large pharmaceutical company, is far greater than that of actually running the product through the process. That is, if the setup time on the processing equipment is one hour and the machine is capable of producing 10,000 vials per hour, the inefficiency is evident if only a few hundred containers are required. The ability to outsource the supply of flexible quantities is invaluable. This ensures the provision of smaller quantities of product until the need for the item reaches a point of efficiency, and the production of final product on large scale equipment, which may exceed 100,000 vials per day, can move “in house”.

Outsourcing of custom cleaning and packaging, therefore, has some clear advantages for the pharmaceutical industry:

• Access to critical cleaning expertise
• Production of containers to exacting regulatory specifications is not a distraction from the company’s product expertise
• Economy of scale
• Accommodation of flexible demands and customization for new applications
• Testing, full documentation and ‘cradle to grave’ traceability

Assessing Your Needs

Each of the above is a sufficient reason for looking to outsource critical cleaning of drug product containers and packaging, but how should the appropriate supplier be chosen? There is no single answer. However, one good starting point would be reduction in risk, both in terms of safety and financially. The various cleaning options should then be weighted according to their influence on risk to the whole business. Requirements to be considered may include the following:

How ‘clean’ is your process?

USP describes limits and methods of analysis for a variety of contaminants. The key regulations relating to the cleaning of containers are: USP 788 for particulate matter in injections, USP 643 regulating Total Organic Carbon (TOC) as an indirect measure of organic molecules, USP 85 relating to acceptable levels of bacterial endotoxins, and USP 71 regarding sterility testing. Will the cleaning processes available ensure that all critical cleaning requirements are met, or even exceeded, cost effectively?

What cleaning methodologies do I need?

Table 1 provides a breakdown of the types of cleaning options available for differing applications.

Table 1: Types of cleaning options available for different cleanroom process applications

Advice and assistance required?

Many API (Active Pharmaceutical Ingredient) manufacturing companies are comfortable with meeting regulatory requirements and will simply outsource for purposes of flexibility of volume. However, there may be companies that are required to supply an intermediate pharmaceutical compound. Although the product itself is not pharmaceutical grade, it is required to meet the expectations of the API manufacturer. This means that the product can be manufactured in an industrial environment, but should have final packaging that meets the strict requirements set by the API manufacturer. These may be guidelines on particulate matter or trace compounds. This is where an expert custom cleaning company can assist by providing the correct level of cleaning to match the customer’s price with their needs.

Help! I need greater throughput now!

The following example demonstrates how this can be rapidly addressed. A contract pharmaceutical manufacturer that fills a product, such as the influenza vaccine, has an established production line capable of meeting a desired throughput. When the swine flu pandemic struck in the fall of 2009, the demand for flu vaccines dramatically increased. While the production of the liquid vaccine was scaled up to meet the demand, the ability of the equipment to process the containers was insufficient. Outsourcing container processing was an opportunity to supplement the supply of the packaging to ensure adequate quantities could be produced to rapidly meet the temporary peak in demand.

I need a customized product

The development of a new application may result in the need for a new and innovative solution, particularly due to the growing need for higher standards of purity demanded by today’s ultra-sensitive analytical instrumentation. Frequently, pharma and biopharma customers require expertise in resolving the difficult challenge of sourcing containers as clean as the facilities in which they will be used. Here the key questions to be asked are:

• Will you send your own materials or do you require them to be supplied?
• What cleaning process(es) do you need?
• What packaging configuration is required? – e.g. Cleanroom bag, autoclave bag, foil wrap, etc.
• What are your certification requirements? – e.g. Certificate of Analysis, Certificate of Processing, selected testing by USP methods, Certificate of Sterility, etc.

Finding the best supplier for you

Once you have decided upon your key requirements, you now need to decide on the best supplier to service these. It is probable that the basic requirements for supply of a clean container can be met by any of several companies in the industry. However, confidence in the quality of containers supplied for use within critical areas is key, along with the ability to understand, advise on and meet very specific needs.

Figure 1: Flow diagram demonstrating how utilizing external resources for custom cleaning and packaging services frees up valuable internal resources

Trust & reputation

Evidence of experience and continuous performance in meeting critical cleaning regulations should be a crucial element in the decision making process. Furthermore, a company should be able to demonstrate that it has never had any instances of product that has caused illness. A good reputation must be earned by building up trust with customers, and an open-door audit policy is an excellent way of developing this, whilst also ensuring that manufacturing companies can satisfy regulatory needs without compromise.

GMP quality compliance

Outsourcing to a reputable company can significantly decrease the amount of in-house compliance work that need be undertaken. If the outsourced company can offer ‘cradle to grave’ traceability through batch record tracking, this ensures that, should the FDA have any questions at any time, the necessary paperwork will always be available to provide an immediate answer. In addition, manufacturing processes and cleanroom facilities that ensure products are handled in Class 100/10 environments can only further secure product quality.

Flexibility

The ability to provide varying quantities of customized end products through processing, packaging and certification to meet the exact requirements of a customer is highly advantageous, particularly if the customer has its own specific containers that need custom cleaning. Furthermore, a supplier that can interact at the customer’s convenience is also an ideal scenario. For example, the ability to visit a customer’s facility and undertake all protocols and validation on its behalf could be seen as ideal.

Return on investment

Selecting a contract cleaning services company that can provide flexibility, confidence and efficiency is no mean feat and there are many considerations to take into account. We have looked at the required expertise, capabilities and services, however, it is ultimately the bottom line — and potential for savings that can be demonstrated by such a company — that is often the critical factor in the decision making process. Figure 1 highlights where outsourcing an expert critical cleaning company can certainly deliver return on investment (ROI). Indeed, value is added since most discovered compounds do not make it to commercialization. This is because internal resources only have an ROI if the product is a success; the truth is that fewer than one in 10,000 are successful.