Introduction
Good Manufacturing Practice (GMP) is a system for ensuring that products are consistently produced and controlled according to quality standards. It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product.
GMP facilities are vital for ensuring quality pharmaceutical production. From clinical to commercial phases, establishing or transitioning GMP facilities presents challenges and lessons. This article explores setting up new facilities, highlighting pitfalls and best practices to aid industry professionals.
Establishing a new GMP facility involves a deep understanding of its foundational elements and operational steps. After all, in pharmaceutical manufacturing, every detail matters – from the architectural design to the subtleties of maintaining quality assurance throughout the production process.
GMP covers all aspects of production, from the raw materials, premises, and equipment to the training and personal hygiene of staff. Detailed, written procedures are essential for each process that could affect the quality of the finished product. There must be systems to provide documented proof that correct procedures are consistently followed at each step in the manufacturing process – every time a product is made.
Let’s understand the important component of a GMP facility, exploring the critical aspects of construction, design, GMP cleanrooms and equipment qualification.
What is a GMP Facility and points to be focused to Understand ?
A “GMP Facility” is a building that is used in the production of pharmaceutical and medical device products. The proper design, layout, function and control of such facilities is essential in the manufacture of pure, safe and effective pharmaceutical products.
Lets understand important points related to GMP Facility as below the building layout, safety, cleanroom conditions, as well as facility sanitation and ventilation of both production and support areas.
1. Construction and Design of New GMP Facilities
- As the construction manager for the project it was our responsibility to follow the proper procedures throughout construction to ensure that the facility passed the final FDA validation and commissioning process.
- The FDA validation process takes place in the last phase of construction of a GMP facility and is what ultimately guides the construction through its entirety.
- A new GMP facility begins with the construction of its foundation, the main building, and the integral cleanrooms, temperature complied (within the FDA’s approved temperature range),power shut down test (power source is shut down and the systems must transfer to the emergency generator within 30 seconds of losing power)
- Both during and post-construction, the essential facility utilities are installed as per a pre-determined design for their intended purpose. This includes all utilities like HVAC, water, gases,piping, drainage, and other supply systems, all of which adhere to industry-standard quality specifications.
2. GMP Cleanrooms
- GMP facilities and GMP cleanrooms are mandatory in various sectors of the pharma, biotechnology, and drug manufacturing industries to ensure high product quality. A cleanroom’s objective is to create an environment with minimized contaminants, suitable for drug-related production
- GMP stands for Good Manufacturing Practices, which is a quality management system used mainly by medical and pharmaceutical manufacturers to ensure a controlled cleanroom environment.In the United States, GMP standards are established and enforced by the Food & Drug Administration (FDA),
- Main goal of GMP standards remains the same: to minimize the risks and control over the microbiological status,the air purity in terms of particle concentration, pressure, temperature and other sensitive parameters
GMP standards distinguish four “grades.” Here’s an overview of the four GMP grades:
- Grade A – A zone for high-risk operations that need the highest level of environmental control. It’s equivalent to ISO Class 5, both at rest and in operation.
- Grade B – A zone for aseptic preparation, filling, and compounding. It’s equivalent to ISO Class 5 at rest and ISO Class 7 in operation.
- Grade C – A clean area for less critical stages in the manufacturing process. It’s equivalent to ISO Class 7 at rest and ISO Class 8 in operation.
- Grade D – Another clean area for less critical stages in the manufacturing process. It’s equivalent to ISO Class 8, both at rest and in operation.
3. Equipment Qualification
Equipment Qualification
- Why: First of all, qualification is required by regulatory authorities. FDA, EMA, MHRA, and WHO require that GMP (Good Manufacturing Practice) equipment used for manufacturing pharmaceutical drugs need to be qualified before released for their intended use. During the qualification process, a piece of equipment will be tested to prove that it meets the requirements of what a user has expected (user specification) and what the equipment is designed for (design/functional specification). The three major stages of an equipment protocol qualification are: Installation Qualification (IQ), Operational Qualification (OQ), Performance Qualification(PQ).
- Equipment qualification is critical in the pharmaceutical industry. The equipment not only includes manufacturing equipment but testing and sampling equipment also to name a few.
- Even the slightest error or misuse can pose a costly risk and time delay for the pharmaceutical product owner and their manufacturer. So, what is equipment qualification?
- It is a series of inspections, tests, and assessments to ensure that a given piece of equipment is compliant and ensures reliable performance. Equipment validation is required to prove that a given piece of equipment does, on a consistent basis, what it is supposed to do. As a key component of quality assurance, equipment qualification is critical to consistently producing high-quality products.
Steps to Qualify a New GMP Facility
1. Design and Layout Planning for New GMP Facility
- Qualifying a new GMP facility starts with meticulous design and layout planning. The design should facilitate easy cleaning, maintenance, and operations. Consideration for cross-contamination, workflow efficiency, and environmental control is paramount.
- To create GMP facilities is to design your facilities according to the specifications and standards of GMP. You need to ensure that your facilities are suitable for their intended use, and that they minimize the risk of contamination, cross-contamination, and errors.
- You also need to ensure that your facilities are ergonomic, efficient, and flexible, and that they facilitate the flow of materials, personnel, and information. You can use tools such as process flow diagrams, floor plans, equipment layouts, and piping and instrumentation diagrams to design your facilities.
2. Selecting the Right Equipment
- Selecting equipment that meets GMP standards is most important. Equipment must be easily cleanable, suitable for its intended purpose, and designed to prevent errors and contamination.
- Acquire pharmaceutical-grade equipment suitable for tablet manufacturing, such as mixers, granulators, tablet presses, coating machines, and packaging equipment. Install and validate each piece of equipment according to GMP standards to ensure functionality and compliance.
3. Validation Processes
- Validation is a fundamental aspect of GMP (Good Manufacturing Practice) qualification, crucial for ensuring the integrity and reliability of manufacturing facilities.
- This involves demonstrating that your facility operates within predetermined parameters and can consistently produce products that meet quality specifications.
- Validation covers equipment, processes, and systems. step to create GMP facilities is to validate your facilities before using them for production. This validation process extends across equipment, procedures, and overall systems. Before commencing production, the initial step in establishing GMP-compliant facilities involves rigorous validation procedures which demonstrates the facility’s capability to consistently produce products meeting predefined quality attributes.
- Key activities within this validation framework include Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ). Through these activities, facilities are tested to ensure they are installed, operated, and perform in accordance with both design specifications and GMP requirements. Furthermore, meticulous documentation and reporting of validation results are essential components of this process, providing a comprehensive record of compliance and assurance of product quality.
4. Implementing Quality Control Systems
- A robust quality control system is the backbone of GMP. This includes the establishment of meticulous Standard Operating Procedures (SOPs), rigorous quality checks, and an efficient documentation system.
- Through this framework, every step of production is meticulously tracked and recorded, ensuring adherence to high standards of quality and safety. This comprehensive approach not only safeguards the integrity of the manufacturing process but also fosters trust among consumers in the products they rely on.
5. How to maintain your facilities ?
- The next crucial step in establishing GMP (Good Manufacturing Practice) facilities is to maintain strict control and compliance standards. You need to implement and follow a maintenance program that covers the preventive, corrective, and predictive maintenance of your facilities.
- Monitoring and regulating environmental conditions such as temperature, humidity, pressure, and cleanliness are paramount to maintaining quality standards. Routine inspections and audits are essential to verify proper functionality and adherence to GMP guidelines, ensuring the integrity of the manufacturing process.
- Design packaging materials in compliance with FDA regulations, including proper labeling with product information, dosage instructions, and warnings. Ensure packaging materials are tamper-evident and suitable for protecting the product during distribution and storage.
- Maintain comprehensive documentation of all manufacturing activities, including batch records, equipment logs, and quality control records. Establish protocols for document control, retention, and retrieval to facilitate inspections and audits by regulatory authorities.
- Develop cleaning procedures for equipment and facilities to prevent cross-contamination and ensure product safety. Implement preventive maintenance programs to keep equipment in good working condition and minimize downtime.
- Qualified and well-trained personnel are essential for maintaining GMP standards. Ongoing training programs ensure that all employees understand and comply with GMP requirements for the proper use and operation of your facilities.
- You need to ensure that your personnel are qualified, competent, and aware of their roles and responsibilities in relation to the GMP requirements.
- You also need to provide them with the necessary knowledge, skills, and tools to perform their tasks effectively and safely. You need to conduct training programs that cover the theory and practice of GMP, as well as the specific procedures and protocols of your facilities.
- The sixth and final step to create GMP facilities is to improve your facilities continuously. You need to collect and analyze data and feedback from your facilities, such as production records, quality indicators, customer complaints, and non-conformities.
- You also need to identify and implement corrective and preventive actions (CAPA) to address the root causes of any problems or deviations. You need to review and update your facilities design, validation, maintenance, and training as needed to ensure their continuous suitability, effectiveness, and compliance.
Qualification Stages for Equipment, Facilities, Utilities and Systems
Qualification activities should consider all stages from initial development of the user requirements specification through to the end of use of the equipment, facility, utility or system. The main stages and some suggested criteria (although this depends on individual project circumstances and may be different) which could be included in each stage are indicated below:
User requirements specification (URS)
The specification for equipment, facilities, utilities or systems should be defined in a URS and/or a functional specification. The essential elements of quality need to be built in at this stage and any GMP risks mitigated to an acceptable level. The URS should be a point of reference throughout the validation life cycle.
Design qualification (DQ)
The next element in the qualification of equipment, facilities, utilities, or systems is DQ where the compliance of the design with GMP should be demonstrated and documented. The requirements of the user requirements specification should be verified during the design qualification.
Factory acceptance testing (FAT) /Site acceptance testing (SAT)
- Equipment, especially if incorporating novel or complex technology, may be evaluated, if applicable, at the vendor prior to delivery.
- Prior to installation, equipment should be confirmed to comply with the URS/ functional specification at the vendor site, if applicable.
- Where appropriate and justified, documentation review and some tests could be performed at the FAT or other stages without the need to repeat on site at IQ/OQ if it can be shown that the functionality is not affected by the transport and installation.
- FAT may be supplemented by the execution of a SAT following the receipt of equipment at the manufacturing site.
Installation qualification (IQ)
IQ should be performed on equipment, facilities, utilities, or systems.
IQ should include, but is not limited to the following:
- Verification of the correct installation of components, instrumentation, equipment, pipe work and services against the engineering drawings and specifications;
- Verification of the correct installation against pre-defined criteria;
- Collection and collation of supplier operating and working instructions and maintenance requirements
- Calibration of instrumentation
- Verification of the materials of construction.
Operational qualification (OQ)
OQ normally follows IQ but depending on the complexity of the equipment, it may be performed as a combined Installation/Operation Qualification (IOQ).
OQ should include but is not limited to the following:
- Tests that have been developed from the knowledge of processes, systems and equipment to ensure the system is operating as designed;
- Tests to confirm upper and lower operating limits, and /or “worst case” conditions.
The completion of a successful OQ should allow the finalisation of standard operating and cleaning procedures, operator training and preventative maintenance requirements.
Performance qualification (PQ)
PQ should normally follow the successful completion of IQ and OQ. However, it may in some cases be appropriate to perform it in conjunction with OQ or Process Validation.
PQ should include, but is not limited to the following:
1. Tests, using production materials, qualified substitutes or simulated product proven to have equivalent behaviour under normal operating conditions with worst case batch sizes. The frequency of sampling used to confirm process control should be justified;
2. Tests should cover the operating range of the intended process, unless documented evidence from the development phases confirming the operational ranges is available.
FAQs
Useful links
- EudraLex, Volume 4, EU Guidelines for Good Manufacturing Practice, Annex 15: Qualification and Validation
- 21 CFR Part 210 – Current Good Manufacturing Practice in Manufacturing. Processing, Packing, or Holding of Drug
- 21 CFR Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals 4. TGA – PE009, the PIC/S guide to GMP for medicinal products 5. ICH Q9: Quality Risk Management, Step 5 version
- ISPE Baseline Guide Volume 5: Commissioning and Qualification
- ISPE GAMP 5: A Risk-Based Approach to Compliant GxP Computerized Systems
- https://www.linkedin.com/in/marco-klinger-b86bb3151/recent-activity/all/
Sagar Pawar
Sagar Pawar, a Quality Specialist at Zamann Pharma Support, brings over 11 years of experience in Quality domain for the pharmaceutical and medical technology industries. Specializing in qualification, validation, Computer System Validation (CSV), and Nitrosamine activities, Sagar is currently focused on enhancing the Zamann Service portfolio by developing and implementing robust strategies to address Nitrosamine-related challenges. Outside of work, Sagar enjoys trekking and cooking. Connect with Sagar on LinkedIn to discuss topics related to equipment qualification, GMP Compliance and Nitrosamine-related challenges.
