Excerpt from Technical Guide: Validating and Establishing a Routine Environmental Monitoring Program for Clean Room Environments

In recent years, there has been considerable growth in the demand for more sophisticated Clean Rooms. Many industries are beginning to discover the benefits of Clean Room technology, while other industries are developing their products in such a way that contamination control is becoming more stringent. This is more prevalent for the biotechnology industries where a few kilograms or even grams of product may be worth millions of dollars. Over the last twenty years, the demand for contamination control has increased to such an extent that the present state-of-the-art Clean Rooms are a thousand times cleaner than those designed in the past. Clean Rooms have progressively developed, and the stage has been reached where it is now possible to design a Clean Room to fulfill almost any environmental requirement. Historically, Clean Room design and management goes back more than 100 years, and was developed by hospitals to control the spread of infectious diseases. Today, the majority of technological breakthroughs for Clean Room design have emerged from the electronic and pharmaceutical industries. For all intents and purposes, the bulk of information discussed in this article will be focused on the pharmaceutical industry. This article will also discuss a step-by-step approach to bringing a Clean Room to a validatable state and maintaining this state through a routine environmental monitoring program. Procedures Used to Bring a Clean Room to a Validatable State The most important step in bringing a Clean Room to a validatable state is the company's commitment to a validation program. While validation is a cGMP requirement, and is a method of managing the quality of the manufactured products, it also makes good economic sense. The general benefits of validation include: 1. Higher productivity. 2. Greater product consistency on a repeatable basis. 3. Fewer rejects. 4. Lower utility cost. 5. More efficient use of equipment. 6. More effective use of manpower. 7. Greater confidence in the product. Benefits are realized over the life of the product in: 1. Helping all concerned understand the process (and why it fails). 2. Providing a basis for process monitoring and for in-process control. 3. Insuring the reliability and consistency of the product. 4. Reducing QA, QC and manufacturing costs. In order to bring a Clean Room to a validated state, a step-by-step approach is needed. The following steps should be considered guidelines for the validation of a Clean Room facility: Design Qualification. Validation Master Plan. Construction Qualification. Installation Qualification. Test, Balancing and Adjustment. Clean Room Certification. Operation Qualification. Performance Qualification. Static and Dynamic Sampling. Routine Environmental Monitoring Program. Design Qualification One of the first steps that should be considered is defining which areas are to be qualified and what their intended uses are. A facilityâs room classification or design specification should be based on the product being manufactured and the processes being used. It is important that the architecture and engineering (A/E) professionals doing the design and layout work are aware of those areas. The reasons for this are as follows1: To define exactly those areas upon which qualification data must be developed. To prevent any misunderstanding, either by the owner or the FDA, as to which areas are going to be subject to qualification. During a pre-construction review of the drawings with the FDA, the list of areas that were specified should be discussed. Then, if there are any differences of opinion between the owner and the FDA, they can be resolved before construction starts. It should also be noted that drawings will be required of the entire facility, noting production features and functions. If the A/E firm knows ahead of time that as-built drawings will be required, the field staff responsible for monitoring the construction activities will make the changes to the drawings as the actual changes are being made in the field. This is probably the only way assurance can be given that your as-built drawings will truly be ãas-builts,ä instead of ãI-think-builtsä. GMPs call for the following, pertaining to layouts: Smooth flow of personnel and product. Adequate space to perform each operation. Spatial separation, where appropriate, to prevent product mix-ups, component mix-ups, etc. Adequate lighting. Environmental controls. The design and construction of any facility requires a team effort. The design qualification (DQ) phase of the project requires the assistance of various departments and professionals, such as quality control and quality assurance, regulatory affairs, facilities/engineering, validation, manufacturing, general contract and sub-contractors. A simplified approach can be summarized as follows: Determine the facility design task force (QA, QC, Engineering, Manufacturing and Validation, etc.). Determine process environment requirements. Determine operational requirements, material, waste and personnel flow. Quantify production, process and equipment space requirements. Develop conceptual layout. Approve final facility layout. Develop detailed system engineering. Prepare designs and specifications. Obtain acceptance by the design review team. Prepare bidding documents. Determine bidding and acceptance process. Determine construction start date. Products and manufacturing processes usually determine the design and layout of your facility. It is also important to arrange a pre-construction or pre-ELA meeting with the FDA. This meeting can decrease the amount of effort in justifying your design after the fact. Validation Master Plan The validation master plan (VMP) is an all inclusive plan that lists your company's philosophical approach to validation efforts. It includes a step-by-step, logical approach to validation tasks and identifies the full scope of all efforts. This document familiarizes the FDA with your facility, equipment and processes. The following is an example of some of the items you may want to include in the VMP: Introduction. Manufacturing facility and process description. General layout. Critical utilities and process equipment list. Facility materials and personnel flow. Air handler service boundary. Facility environmental classifications. Facility pressurization and differential air flow. Project scope. Validation program overview. Validation cycle and document flow diagrams. Design review. Installation qualification protocols. Operational qualification protocols. Performance qualification protocols. Process qualification protocols. Protocol final reports. Validation test methods. Project timelines. Standard operating procedures (SOPs). Responsibilities. Maintenance of validation and re-validation. Definitions. References. Validation synopsis sheets. The VMP is probably the most critical step in facility validation. It should be considered a living document, to be referenced and updated (if necessary) throughout the project and the life of the facility...