Introduction
Demanding nature of manufacturing conditions, complex production processes and criticality of products make construction, installation and commissioning of pharmaceutical facilities different from other industries. The costs involved in production and utilities installations and finishes too are far higher than ordinary non-pharmaceutical facilities. Since the facilities involve manufacturing pharmaceutical products that help in patient care and saving lives, it is imperative that the facilities comply with the regulatory mechanism and perform to total compliance from the day one of production. It is because of this that a strict validation process is required and failure to satisfy its principles results in a lack of compliance and the facility can be a non-starter. The re-working increases the cost leading to a late start of production and a sense of dissatisfaction in the client.
Some important considerations
Commissioning and validation ensure that the facility shall operate as required and according to the stipulations of the regulatory agencies that have jurisdiction over it. Validation is based on documented proof of tests that show that design and processes operate according to what is specified. We will take it up below. A company can begin the design and installation process by creating a user requirement specification (URS) document. This is the first step in putting things in place as processes related to commissioning and validation unfold. Following this critical quality attributes (CQAs) should be established. CQAs are physical, chemical, biological and microbial parameters that have to be kept in check during the manufacturing process. Post CQAs, critical process parameters (CPPs) are established. Defining CPPs crystallizes the design specifications of the facility. As an example, if the facility is to manufacture a tablet that requires a powder mix then humidity wouldn’t be a controlling factor. Therefore, HVAC would be designed accordingly. Similarly, if the room pressure, room classification shall be required if the API is highly toxic. All such specifications are mentioned in the URS at the pre-design stage. After the completion of the final project design document, they can be reviewed in an enhanced designed review (EDR).
Making the beginning
Various factors are carefully considered before installation of a facility, which affects its commissioning and validation. The most basic criteria to be considered are the geographic location as it has a profound effect on logistics management. Even before that the installation consultants have to familiarize themselves with local governmental regulatory mechanism and international laws, codes, etc. For example, if the market for the products is Europe than the European GMP for qualification and validation shall apply. If we propose the market to be the US, the FDA GMP described in 21 CFR 211.42 on building and facilities have to be complied with.
The locations of the pharmaceutical products market also have to be accounted for in the basic planning of the facility. Such factors as prevention of materials contamination, hazard to the product because of maintenance and operations, appropriate HVAC, non-intrusion of insects and animals and checking of unauthorized entry of people have to be taken into account. The facility should not hamper proper cleaning and maintenance. It should be adequately sized for placement of equipment, flow and storage of materials. There should be proper space for support operations, including utilities, packaging and labeling and inventory maintenance. Hence ensuring quality in pharmaceutical products depends on many factors and understanding and implementing the regulations of Good Manufacturing Practice (GMP) in the installation of facility and conducting of validation. Besides, the regulatory mechanism requirements for a facility is installed and erected with the end of producing a “quality product in mind.”
Various qualification
Once design and construction have been completed, the facility must be qualified and its processes must be validated. The validation system ensures accuracy, specificity and reproducibility of the procedures adopted. Validation is done in a pre-defined protocol. It is a documentation process that ensures design requirements, specifications and stakeholder expectations are met. Validation comprises four phases: 1. Design Qualification (DQ) 2. Installation Qualification (IQ) 3. Operational Qualification (OQ) 4. Performance Qualification (PQ).
1. Design Qualification (DQ) lays down the roles and responsibilities of engineers and designers in developing the layout of the facility. It also determines the roles of vendors and subcontractors. Proper documentation of site, supporting utilities, equipment and operating procedures is created. Although design qualification doesn’t fall under GMP requirements but commissioning of facility including assuring power and water supply, HVAC systems, waste management—all are accounted for in the design process.
2. Installation Qualification (IQ) is compilation of documents that ensure proper receipt and installation of equipment of machinery and equipment at the site. The documentation ensures that only are the equipment operational, but they meet the standards and specifications of the manufacturer. Some IQ considerations are design features of materials, equipment installation conditions, calibration, preventive maintenance, drawings, documented software, etc.
3. Operational Qualification (OQ) is performed during commissioning to ensure that the equipments are performing according the operational standards and meet the quality requirements. Operator training can be done at the premises of the supplier, while other things related to replacement, power supply and operation confirmation is done at the site. OQ considerations may include software parameters, process control limits like temperature, pressure, training, material handling, etc.
4. Performance Qualification (PQ) is the last stage in which DQ, IQ, OQ are reviewed. PQ ensures that the production is taking place under set standards and required settings. PQ considerations include product and process parameters set up in OQ, process capability assurance, acceptability of the product, process repeatability and stability of the systems.
From a pure regulation point of view, qualification is necessarily the responsibility of the manufacturer and they have to pass on explicit instructions to the supplier or the consultant.
Environment control
Another important factor to be considered before commissioning a project is the environment control. It is necessary for quality and effective product to reach the patient. Maintenance of environment in a pharmaceutical facility requires integration of industrial automation, process and building systems such as HVAC. Since these systems are sourced from multiple suppliers a common interface has to be created with them that keep inputs and outputs in tolerable limits.
Teamwork
Commissioning and Validation is a team effort that requires a synchronized and integrated effort of various teams belonging to architecture, structural engineering, operations, and quality assurance and operational and information technology. The idea behind this is that quality cannot be tested into it a product rather it is designed into a pharmaceutical product. This means involvement of all team members in the facility’s design from the earliest levels.
Conclusion
To conclude, commissioning a turnkey project under GMP regulatory mechanism requires that all operations are under it qualify for the intended function. The end user or the facility owner should be able to trace the verification of the systems and equipment. This minimizes the chance of breach of quality control or break down. The success of implementation according to specifications at turnkey level verifies that what was specified was correctly installed and the next verifiable levels (if any) would be through.
