Why GMPs? What are GMPs and Why Do We Need Them?

Good manufacturing practices (GMPs) are manufacturing guidelines for ensuring the safety and efficacy of drug products and medical devices. The GMPs are legal regulations, based on the United States Food, Drug and Cosmetic Act. But, why do we need the GMPs? Shouldn't we, as knowledgeable individuals, groups, and companies, be able to figure out how to produce drugs and devices that are safe and effective?

The answer is "yes and no." We are knowledgeable, but we do need our work to be guided by stated expectations. All aspects of a complex society require rules. Why should our industry be any different? After all, these products can be life-saving or, if impure, a serious health threat. Even lawnmower manufacturers and bridge builders are adopting standardized manufacturing rules.

The GMPs are promulgated by FDA. However, FDA is part of the U.S. Public Health Service (USPHS). Ensuring the safety of drinking water is a good example of USPHS's role. Water can be an efficient means of transmitting diseases, such as cholera, cryptosporidium, and enteroviruses. USPHS's approach prevents illness by protecting water sources and minimizing the risk of disease through filtration and disinfection. Likewise, FDA is entrusted with ensuring public health — preventing harm to the public from drugs and medical devices. The agency also is charged with ensuring products are efficacious. These are consequences of a public health approach: FDA oversees proactive measures to ensure these objectives are routinely met, which is where GMPs fit in.

Requirements vs. Outcomes

If you look at the manufacturing systems of three different pharmaceutical companies, you will likely find three different sets of terminology, procedures, and activities designed to ensure compliance with GMPs. How can this be, if all three are following the GMPs?

The answer is easy: the GMPs are not checklists. They do not describe how work is to be performed; they define the required outcome of the work performed. How an organization chooses to achieve these outcomes is determined by that organization.

For example, the GMPs do not state that a documentation system is required; however, the phrase "written procedures shall be established and followed for..." is used throughout the GMP regulations. If a documentation system is not in place, how else can the required outcome, specifically that written procedures be established and followed, be achieved?

Despite what some critics of the GMPs have stated, they are flexible. They require manufacturers to evaluate the outcome articulated in the regulation, assess how that outcome can best be achieved, and then implement it. Finally, they must ensure that compliance with GMPs can be demonstrated — for example, to FDA inspectors and collaborators.

cGMPs

cGMP stands for current good manufacturing practices. One heavily debated issue in GMP discussions is to "c" or not to "c". Does GMP = cGMP? Yes.

FDA expects organizations to take the appropriate steps to ensure that the safety, identity, strength, quality, and purity of a drug product is preserved. The scope of GMPs is stated in 21 CFR 211.1(a): "The regulations in this part contain the minimum current good manufacturing practice for preparation of drug products for administration to humans or animals." Also, note the word minimum.

Implementing GMPs

GMP implementation never stops, as the GMPs continue to evolve. The stimulus for revision comes from a variety of areas, including FDA observations made during site inspections. Many years ago, as the story goes, an inspector discovered that a manufacturing plant's toilet facilities consisted of an outhouse outside the plant (remember that GMPs came into existence in 1978). The rule addressing this topic now reads as follows:

Sec. 211.52 Washing and toilet facilities. Adequate washing facilities shall be provided, including hot and cold water, soap or detergent, air driers or single-service towels, and clean toilet facilities easily accessible to working areas.

As another example, the GMPs did not always say that written procedures were necessary and compulsory. Some enterprising individuals argued that because the regulations did not require that their written procedures be followed, they didn't have to do so. The phrase, "written procedures shall be established and followed for...," now appears in the GMPs at least 100 times.

Implementing revised GMPs can be equally tricky for a newly established organization or one that has been in business for many years. One of the biggest issues is interpreting exactly what the desired outcome of the regulation is. Once that hurdle has been overcome, the next is assessing whether practices to ensure this outcome are already in place. If so, there is no problem. If not, then integrating new practices into an existing way of doing work can be challenging. Rewriting procedures and re-training personnel takes time.

One of the most important ways of reducing implementation challenges is keeping it simple. Making it easy for personnel to comply with internal organizational requirements reduces the risk of an FDA observation reading, "Internal procedures were not followed." Maintaining perspective on the big picture — GMPs define outcomes — will facilitate understanding and long-term compliance with GMPs.

Janet Rose Christensen is vice president, regulatory affairs and quality, AVI BioPharma, One SW Columbia Street, Suite 1105, Portland, OR 97258, 503.227.0554, jrc@avibio.com.