5.3: Current Good Manufacturing Practices (CGMPs)

These guidelines for product manufacturing and testing represent a formal quality system that describes the general principles that must be observed during manufacturing. It is the company's responsibility to ensure GMP compliance and to do so efficiently and effectively. To this end, regulations are relatively flexible. It is up to the manufacturer to establish design procedures, processing methods, and testing procedures. This flexibility gives companies room to experiment and innovate.

Published in 1963, the first set of Good Manufacturing Practices (GMP) was intended to prevent deaths and injuries from contaminated products. These regulations seek to ensure the quality and purity of drugs products from batch-to-batch and put a system in place to detect and reduce errors and variation in manufacturing. In 1990, the FDA revised CGMP regulation to add the design controls authorized by the Safe Medical Devices Act. The FDA believed that it would be beneficial to the public and the medical device industry for the CGMP regulation to be consistent with international standards ISO 9001:1994 and ISO/CD 13485 "Quality Systems--Medical Devices--Supplementary Requirements to ISO 9001.” After an extensive effort, the part 820 revision was published on October 7, 1996 (61 FR 52602), and went into effect June 1, 1997.

Additionally, it should be noted that CGMPs represent only the currently accepted minimum standards for manufacturing, testing, and packaging drugs and medical devices. Most companies go beyond minimum guidelines to assure a customer a high-quality product. They frequently employ multiple quality systems, including voluntary ones, which gives the consumer peace of mind and a level of trust in the safety of the product.

GMP Guidelines Follow a Few Basic Principles:

1. Define, control, and validate all critical manufacturing processes.
2. Changes to the manufacturing process must be evaluated and approved.
3. Instructions and procedures must be written and easy to understand.
4. Production operators must receive thorough training
5. The company must maintain accurate records demonstrating their adherence to guidelines and regulations.
6. Records must be comprehensive, complete, and easily accessible.
7. In the case of pharmaceuticals, quality is not diminished in any way by the distribution process.
8. A recall system is in place so that any batch of a drug may be easily recalled from sale or supply.
9. The company responds to complaints, quality defects are investigated, and appropriate measures are taken to prevent future errors.

CGMP Regulations

GMP regulations are included in Title 21 Chapter 1 of the CFR, in three regulations dealing with different types of manufactured products:

1. for drugs (21 CFR 211)
2. for medical devices (21 CFR 820)
3. for blood and blood components (21 CFR 606)

The general principles of CGMP that all these regulations have in common:

1. Quality, safety, and effectiveness are designed and built into the product, not tested or inspected into the product.
2. Each step in the manufacturing process is documented and controlled to ensure that the finished product meets design and compendia specifications.
3. Process documentation provides evidence of compliance with CGMPs.

Three primary criteria used by the FDA in the design of these CGMP regulations:

1. Regulations should contain objectives and not detailed specifications. They should allow latitude for different manufacturers to find their means of compliance.
2. Regulations should contain requirements that are considered feasible and valuable as recognized and considered by experts as assuring quality.
3. If a practice can be established to be reasonable and relevant, then it can be a required practice even though it does not exist in the regulations.

Designing a GMP-Complaint Process

1. The purpose of the process must be defined; that is, the desired output must be determined.
2. An endpoint(s) that demonstrates the process is performed satisfactorily must be defined.
3. A method to measure the desired endpoint is required.
4. Raw materials and their specifications must be established.
5. The steps in the process must be determined, usually by experimentation.
6. The process must be scaled-up for production.
7. An analysis of potential problems must be performed, noting the "critical points."
8. Experiments must be carried out to determine how the process must operate at each critical point to make a quality product.
9. Methods to monitor the process must be developed.
10. Methods to control the process must be developed.
11. Adequate record-keeping procedures must be developed.
12. All SOPs required for the process must be written and approved.

Corrective Action Preventative Action (CAPA)

CAPA is an important part of any CGMP design and focuses on the systematic investigation of root causes of issues in the manufacturing process. CAPA is a way in which manufacturers can implement continuous improvement plans and Quality Management systems and have a large impact on FDA compliance. There are three main CAPA categories: Corrective actions that have never occurred, Corrective Actions of reoccurrences, and Preventative Action to prevent an occurrence. CAPA is mandatory for medical device manufacturing, and we will discuss CAPA more in the medical device chapter. Learn more about CAPA here: www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/UCM334579.pdf

Setting standards for quality in the biotechnology industry is difficult due to the often new and complex manufacturing processes involved. How should the FDA set quality standards, for example, for chromatographic purification systems? These processes are difficult to validate and represent ‘gray’ areas where quality regulations are concerned. For this reason, companies frequently rely on regulations that the FDA has not yet finalized, and they comply voluntarily with CGMPs and Guidelines.

The CGMPs for Medical Device, Pharmaceuticals & Biologics will be further explored in those respective chapters. The commonality between the three products in CGMP regulations is that the regulations are intended to ensure the safety and efficacy of those products. Failure to abide by CGMP requirements may result in adulterated products and FDA enforcement repercussions (explored in a later chapter). As regulations change, manufacturers must learn and comply with the new regulations. Continuous improvement, CAPA, internal audits, and FDA inspections all work together to ensure Quality by Design, and not by testing.