Preface

I admit it, I watch reruns of the original Star Trak television series as a way to unwind from a hard day at work. Now I am not such a fanatic that I know all the episodes and that I immediately recognize dialogue and minor characters, but certain things have stuck with me. Pertinent to this book is a quote that is attributed to Scotty, the Enterprise's irascible Chief Engineer. Now I cannot remember the episode or the circumstances but in one of the seemingly endless impossible situations Scotty finds himself in, he notes "Fool me once, shame on you, fool me twice, shame on me."

So, what does this have to do with my second book on the subject of chemical characterization, popularly known and mis-represented as "extractable and leachables?" Well, in the preface of my first book on this subject, I indicated a certain trepidation at even starting that project, recognizing the difficulty in trying to bring a certain degree of order to a subject where there was little consensus, imperfect knowledge, and minimal meaningful guidance. In the end, I ultimately decided that while I could not bring the subject to closure, I could move the ball just a little closer to the endzone.

As I suspected would be the case when I wrote the first book and as has been verified by ongoing and recent developments, the field has changed dramatically in the decade since the publication of that book. Facilitated by both scientific publication and more casual "word of mouth," many (but not all) questions of science have been engaged, addressed and, to a certain extent, answered. Based on the evolving understanding of good science practically applied, experimental and laboratory strategies, tactics, and practices have been improved so that better information is more routinely obtained in a more effective, efficient, and reproducible manner. A multitude of new case studies have opened our eyes to new threats and new opportunities while at the same time putting some of the old monsters back under the bed where they belong. Through the hard and largely thankless work of regulators, standard setting bodies, and professional organizations (and the volunteers who selflessly give of their time and talent), some progress has been made in terms of consensus-building that seeks to find the proper risk-based balance between the ivory tower of science and the practical realities of developing, registering, regulating, marketing, and supporting safe, effective, and appropriately inexpensive pharmaceutical and medical products that save, sustain, and improve lives. To a certain extent, this consensus-building has reached the point where actionable and appropriately conservative regulations, guidelines, and best practice recommendations have been developed, published, and executed. Unfortunately, in too many ways it is "still the wild west out there."

So, it is time to get back in the saddle again and write a new text considering the ongoing and ever-changing scientific and practical endeavor that we call "E&L." Not to throw out the old texts as invalid, irrelevant, imperfect, and incorrect but rather to say "given what we know today, we can improve on what we had in the past." Fool me twice, indeed!

Most of the readers will be familiar with the phrase "what happens in Vegas stays in Vegas," which gives people at least the impression that they can "walk a bit on the wild side" while visiting Vegas with no significant consequence. The corresponding expression in the E&L world go something like "What starts in the item should stay in the item." You see, as I have noted previously, drug products do not just magically appear to the user at time of use. Rather, drug products must be manufactured from their individual raw materials and ingredients. Once manufactured, drug products must be packaged for protection and preservation during distribution and storage. At time of use, drug products must be administered to the user, either by the action of the storage container or the action of a drug administration device.

Each of these activities, manufacturing, storage, and delivery, includes contact between the drug product (and/or its precursors) and one or more items. For example, process solutions encounter various items including mixing and storage containers, tubing, filters, gaskets, connectors, sensors, etc., as they are converted into the final drug product. During storage and distribution, the drug product is in contact with components of its packaging system. During administration, the drug product is in contact with that medical device that serves as the intermediary between the packaging and the patient.

Each contact described above provides an opportunity for the drug product (or its precursors) and the contacted item to chemically interact. If, during that interaction, "what starts in the item stays in the item," then life is good. The drug product is not altered by the contact and everyone goes away safe and happy.

Unfortunately, drug products and the items they contact are quite different chemically and thus some extent of drug product alteration will occur as a result of that contact. On the one hand, substances in the contact item will be driven by a concentration gradient to move from the item and into the drug product. In this way, substances leach from the item and into the drug product, thereby becoming foreign impurities in the drug product. As foreign impurities in the drug product, these substances may have an unwanted effect on the drug product, for example rendering it less stable. Alternatively, the foreign impurities may be toxic and thus they represent a safety hazard to drug product users. In any event, characterization of the drug product for foreign impurities (leachables) and/or characterization of the contact item for potential foreign impurities (extractables) becomes a pre-requisite for establishing that a drug product is suitable for its intended use.

Of course, "for every action there is an equal and opposite reaction." For leaching, this opposite action is sorption. While leaching involves the movement of substances from an item and into the drug product, sorption involves the movement of substances from the drug product and into the contact item. As it is rare that drug products are formulated with superfluous ingredients, loss of an ingredient can have a significant adverse effect on drug product potency, efficacy, and/or stability.

However, sorption is a topic for another author and another book. In this book we will focus strictly on those interactions that add substances to the drug products and/or their precursors. When one tests items to establish "what could come out," one is performing an extractables or extraction study. When one tests the drug product (or precursor solution) for foreign impurities derived from the items, one is performing a leachables or leaching study. Generally, through a combination of both extractables and leachables testing, one produces the data set with which the impact of the interaction on the patient, the drug product, and the item can be assessed.

A similar discussion can be held for a medical device, where chemicals present in the device can leach out into that medium by which the device directly or indirectly interacts (or "communicates") with the device's user.

Previous works in this field have focused on providing answers to two important questions: "What has to be done?" and "When does it have to be done?" While providing updated answers to these questions is still an important objective of this book, we will also consider and address two additional points: "How do we do what we need to do?" and "Why do we do it that way?" Although a fifth question is relevant, specifically, "Where does what needs to be done get done?" is pertinent, this question will not be addressed to any great extent as its answer is largely an individual organization's prerogative.

A few words about the construction of this book are appropriate. Actually, the hardest part about writing this book is not collecting the contents but rather organizing the concepts and contents in a logical and appropriate manner. It is challenging to construct a text that starts from the beginning, establishing essential concepts and principles, and then takes these basic building blocks and turns them into a finished structure. Nevertheless, the book is roughly constructed in this manner, starting with concepts and ending with tactics, strategies, and processes.

Chapter 1 serves as the introduction to the issue of chemical compatibility. In addition to providing a Problem Statement, Chapter 1 speaks to the evolution of chemical assessment as an area of interest, as a scientific discipline, and as a regulatory "topic of interest." Chapter 1 will delineate those significant issues facing the various stakeholders involved with designing, implementing, interpreting, reporting, and reviewing chemical characterizations, setting the stage for the answers that will be provided in the ensuing Chapters.

Chapters 2 through 4 are the places where we establish the building blocks upon which chemical characterization will be built. As I am convinced that one of the difficulties in addressing chemical characterization is a sloppy use of an evolving but disjointed nomenclature, definitions, derived from and consistent with emerging standards, will be provided for all relevant terms and concepts. Extraction and leaching studies will be described and discussed, in terms...