In the workshops I present to technical, quality, and management groups, one of the most frequent questions asked is, “where in the Good Manufacturing Practices (GMPs) does it say I have to do _______?” You can fill in the blank with items such as error correction on a document, or cleaning validation, or including certain things in an investigation report. Often, you won’t find specific requirements in a given regulation, like the US FDA’s Current Good Manufacturing Practice regulations. For example, 21 CFR 211, originally published in 1978 and updated several times since then does not specifically require errors to be corrected with one line through the original entry, initials and date of the person making the correction, the new entry, and a reason for the correction. Nor does the US cGMP specifically require that GMP/quality audits be performed. (Other, more recent requirements published by Health Canada and the European Union do have these requirements.)
A key to understanding how GMP concepts and expectations change and evolve is from a Warning Letter the US FDA wrote to a pharmaceutical manufacturer in 1998 explaining their philosophy. At issue was stability testing – the firm was contesting some specific expectations that FDA had. FDA said this in the Warning Letter:
We acknowledge that the cGMP regulations are not explicit about annual stability testing; however, it should be noted that the cGMP regulations are not all inclusive and that what determines a manufacturing practice to be “current” and “good” is if it can be considered feasible and valuable. In the case of annual stability testing, the agency has determined that such a practice is feasible and valuable and, thus, enforceable under Section 501(a)(2)B) of the Food, Drug & Cosmetic Act (FDA, 1998).
Two words are important to notice: “feasible” and “valuable.” We can define them this way: Feasible – you can do it; reasonably available technology exists that allows it to be performed. Valuable – the practice contributes to the safety, identity, strength, purity, and quality of the product; you are going to have more control over the product, the process, or the information you are using to make a decision concerning the product or process. Informal conversations that I’ve recently had with FDA drug experts have confirmed that these concepts are as valid today as they were in 1998.
As our industry’s manufacturing and distribution practices are getting more complex and more global, manufacturers cannot just focus on one or two sets of requirements – it is too difficult to operate a quality system that has a multitude of variations to meet the individual requirements of a particular national authority. Most multinational firms and those supplying global markets have done what national authorities have not – they have created quality systems and quality system elements that internally harmonize GMP expectations. Yes, there still are some unique requirements that need to be met, but having a majority of requirements harmonized reduces duplication and increases flexibility.
GMP in Practice is intended to help with that harmonization. In it, we will look at more than 30 elements that are typically included in a modern pharmaceutical quality system. Each quality system element has an overview section, some risk-related questions, and 3-10 expectations. Each expectation is explored in a bit more detail and examples of GMP references from the US FDA, Health Canada, the European Union, the World Health Organization, and the International Conference on Harmonization (ICH) are presented. (More on these references below.)
It’s been my experience that, in order to get a rich understanding of GMP, a person needs to have knowledge of what various national authorities expect. Often, these individual expectations give slightly different perspectives that, when put together, provide a more detailed, robust sense of “feasible and valuable.”
In using this book, there are some cautions:
First, before setting up a system or defending a practice based on something you read here, go to the source documents (you will see these listed below and at the end of each chapter) and read the reference in context.
Second, requirements are very dynamic, so look at the most currently available reference.
Third, keep current with how interpretations change and what inspectors are looking for. Meetings, newsletters, websites and blogs are useful tools.
Fourth, there are other requirements that may apply – as described below, this book is not a comprehensive collection of all expectations. Other guidances may be pertinent.
Fifth, keep in mind seven key essentials of GMP:
- Product the product from contamination.
- Prevent mix-ups.
- Know what to do before you do it – and have a rationale to support it.
- Document what really occurred.
- Strive for consistency and control.
- Have management that supports a person and/or group that makes independent, final decisions on documents, products, and processes, and materials.
- Learn from what has happened, investigate problems, monitor and continually improve.
Having an effective, robust quality system in place helps you accomplish these essentials and produce products that are consistently safe, identified, of the proper strength, pure, and meet the regulatory requirements wherever they are marketed.
References Cited in this Book
The regulatory references used come from five different sources and were selected because of their applicability to the industry and that “official” English versions were available. There are a number of other useful guidelines from national authorities and standard-setting bodies that could have been included but were not because of available time and resources…
References cited in the chapters reflect the spelling in the original document. If a section of a larger citation was used, an ellipse (“…”) was placed before and/or after the missing text. As mentioned earlier, always go to the current, original document before establishing, modifying, or defending a practice or decision.
James Vesper