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Boca Raton London New York Washington, D.C.. HANDBOOK OF. Pharmaceutical. Manufacturing. Formulations. Sterile Products. Sarfaraz K. Niazi. VOLUME 6. Volume 6. Handbook of Pharmaceutical Manufacturing Formulations: . PDF). scale-up and postapproval a regulatory review. changes. and special topical. International Standard Book Number (Volume 6; Handbook of pharmaceutical manufacturing formulations / Sarfaraz K.
Product Description: An authoritative and practical guide to the art and science of formulating drugs. With thoroughly revised and expanded content, this Second Edition six-volume set compiles volumes from FDA New Drug Applications, patent applications, and other sources of generic and proprietary formulations to cover the broad spectrum of issues concerning drug manufacturing. A must-have collection for pharmaceutical manufacturers, educational institutions, and regulatory authorities, this set is an excellent platform for drug companies to benchmark their products and for generic companies to formulate drugs coming off patent. As the largest reference on pharmaceutical formulations, this handbook also provides guidelines on how to file aNDAs in the shortest possible time, helping pharmaceutical companies to cut costs in the areas of pharmaceutical research and development. Divided conveniently into two parts—regulatory and manufacturing guidelines, and formulations—each volume in the set covers: cGMP compliance.
The sep- from the utility of the book. I would sincerely appreciate aration of OTC products, though they may easily fall into readers pointing out these mistakes to me for corrections one of the other five categories, is made to comply with in future editions. Sterile products require skills related to steril- ization of product, and of less importance is the bioavail- Sarfaraz K.
Niazi, Ph. These types of considerations have led to the classification of products into these six categories. Preface to the Volume The semisolid drugs category is comprised of ointments, much of the regulatory discussion presented here is drawn creams, gels, suppositories, and special topical dosage from the requirements of the U. Food and Drug Admin- forms. The formulations of semisolid drugs share many istration FDA and the harmonized guidelines with the common attributes of consistency, presentation, preserva- ICH listings.
Although it is likely that some of the require- tion requirement, and the route of administration, mainly ments and recommendations made here might change, it topical. As a result, grouping them together for the purpose is unlikely that the basic thrust in establishing these guide- of defining common formulation practices and problems lines will change. As always, the applicants are highly is justified.
The topical dosage forms present unique encouraged to communicate with the FDA on the changes opportunities to design novel drug delivery systems such made to these guidelines and especially for any significant as patches and other transdermal systems.
Some of these changes made to compliance requirements. In selecting the formulations, I have tried to drawal and finalization of guidelines provided. PDF , which should be reviewed periodically. Obvi- made to approved NDAs or ANDAs; this is a significant ously, considerations such as incompatability of the drug topic for continued compliance with the CGMP require- with the ingredients is of pivotal importance; these base ments but, unfortunately, the one that is most easily misun- formulations of stable emulsions provide a good starting derstood or misconstrued.
For example, at what level of point in the development of new products or even when change should the FDA be informed, either before making a different topical consistency is desired. I have also made a change or after? What happens if a change is made inad- an effort to highlight those formulations that are currently vertently and later discovered; how to report this change? The situation have chosen to only give the composition or mere identi- gets extremely complex when there are multiple dosage fication of ingredients to conserve space for those formu- forms, for which the requirements may be different.
Chapter 2 gets into details of changes made pursuant The regulatory agencies impose certain specific to discussion in Chapter 1 when it comes to semisolid requirements on the formulation and efficacy determina- drugs.
A more detailed description of level of changes is tion of drugs contained in these formulations. For exam- described here, and advice is provided on when to conduct ple, the CGMP factors, scale-up and postapproval a regulatory review. This In this volume, we present over formulations and, is a topic of special interest to the FDA because in the in keeping with the tradition in other volumes, a chapter processing of semisolid products, the equipment plays a piv- on formulation-related matters.
In the regulatory section, otal role. The mixing of drugs within the base media is highly we offer a difficult area of compliance, changes to affected by the process and mechanism of mixing used. Validation of Analytical Procedures. Impurities In New Drug Substances. Formulation Factors in Semisolid Dosage Forms. Testing of Semisolid Dosage Forms. Approved Excipients in Semisolid Dosage Forms. Volume V: Regulatory Guidance.
Quality management in the drug industry: philosophy and essential elements. Solid Oral Dosage Forms Validation.
Pharmaceutical Manufacturing Formulations. Tablet Coating Formulations. Volume VI: Regulatory and Manufacturing. Sterile Manufacturing Formulations Template. Inspection of Sterile Product Manufacturing Facilities. New Drug Application for Sterilized Products.
Validation of Cleaning Process. Essential Cleanroom Design Elements. The FDA is always very helpful in this phase of study protocols, particularly where a generic drug is involved. It is also a good idea to benchmark the product against the innovator product. However, one should understand clearly that the FDA is not bound to accept stability data even though it might match that of the innovator product. The reason for this may lie in the improvements made since the innovator product was approved.
For example, if a better packaging material that imparts greater safety and shelf life is available, the FDA would like this to be used not for the purpose of shelf life, but for the safety factors. Obviously, this is one way how the innovator controls the proliferation of generic equivalents.
The original patents that pertain to synthesis or manufacturing of the active raw material may have been superseded by improved processes that are not likely to be a part of a later patent application to protect the trade secret because of double-patenting issues.
The innovator often goes on to revise the specifications of the active pharmaceutical ingredient to the detriment of the generic manufacturer. However, my experience tells me that such changes are not necessarily binding on the generic manufacturer, and as long as cGMP compliance in the API is demonstrated and the impurities do not exceed the reference standard if one is available , there is no need to be concerned about this aspect.
However, manufacturers are advised to seek a conference with the FDA should this be a serious concern. At times, the manufacturer changes the finished product specification as the patents expire or reformulates the product under a new patent. A good example of this practice was the reformulation of calcitriol injection by Abbott as its patent came to expiry. The new specifications include a tighter level of heavy metals, but a generic manufacturer should have no problem if the original specifications are met because the product was approvable with those specifications.
Chapter 3 describes the container closure systems; again, this discussion would apply to all dosage forms. It is noteworthy that the regulatory agencies consider containers and packaging systems, all those components that come in contact with the product, protect the product from environment, or are instrumental in the delivery of the product as part of the product definition. Whereas the industry is much attuned to studies of the effects of the API and dosage formulation components, the study of container or closure systems is often left to the end of the study trials.
This is an imprudent practice, as it might result in loss of valuable time. The packaging industry generally undergoes faster changes than do the chemical or pharmaceutical industries. New materials, better tolerances, more environmentally friendly materials, and now, with the use of mechanical devices in many dosage forms, appropriate dosing systems emerge routinely.
As a rule of thumb, the closure system for a product should be the first criterion selected before development of the dosage form.
Switching between a glass and a plastic bottle at a later stage can be a very expensive exercise. Because many of these considerations are drawn by marketing teams, who may change their product positioning, the formulation team must be appropriately represented in marketing decision conferences.
Once a decision has been made about the presentation of a product, the product development team should prepare several alternatives, based on the ease of formulation and the cost of the finished product involved. It should be emphasized at all stages of development that packaging scale-ups require just as much work as does a formulation scale-up or changes.
Changes in the dimensions of a bottle may expose a large surface of liquid to the gaseous phase in the bottle and thus require a new stability testing exercise. This chapter forms an important reminder to formulators on the need to give consideration to every aspect of the container closure system as part of routine development. Chapter 4 introduces the area of preapproval inspections, a process initiated by the FDA in the wake of the grand scandals in the generic pharmaceutical industry a few years ago.
A regulatory inspection can be an arduous exercise if the company has not prepared for it continuously. Preparedness for inspection is not something that can be achieved through a last-minute crash program.
This chapter goes into considerable detail on how to create a cGMP culture, how to examine the documentary needs, assignment of responsibility, preparation of validation plan, and above all, the art of presenting the data to the FDA. Also discussed are the analyses of the outcome of inspection.
Advice is provided on how to respond to Form issued by the FDA, and the manufacturer is warned of the consequences of failing an inspection. Insight is also provided for foreign manufacturers, for whom a different set of rules may be applied because of the physical constraints of inspection.
The inspection guidelines provided apply to both the manufacturers of API as well as to the finished products. Chapter 5 includes highlights of topics of importance in the formulation of liquid products. However, this chapter is not an all-inclusive guide to formulation. Only highlights of points of concern are presented here, and the formulator is referred to several excellent treatises available on the subject.
Section II contains formulations of liquid products and lists a wide range of products that fall under this classification, as interpreted in the volume.
There are three levels at which these formulations are described. First, the Bill of Materials is accompanied by detailed manufacturing directions; second, the manufacturing directions are abbreviated because they are already described in another product of similar nature; and third, only the composition is provided as supplied by the manufacturer.
With the wide range of formulations included in this volume, it should be a simple matter for an experienced formulator to convert these formulations into quantitative Bills of Materials and then to benchmark it against similar formulations to come up with a working formula. The problems incumbent in the formulation of liquid products are highlighted in Chapter 5, but these are generic problems, and the formulator should be aware of any specific situations or problems that may arise from time to time.
I would like to hear from the formulators about these problems so that they could be included in future editions of this book. Again, the emphasis in this series is on a practical resolution of problems; the theoretical teachings are left to other, more comprehensive works on this topic.
The key application of the data provided herein is to allow the formulator to select the ingredients that are reportedly compatible, avoiding need for long-term studies to establish compatibilities. I am grateful to CRC Press for taking this lead in publishing what is possibility the largest such work in the field of pharmaceutical products.
It has been a distinct privilege to know Mr. Stephen has done more than any editor can do to encourage an author into completing this work on a timely basis. Though much care has gone into correcting errors, any errors remaining are altogether mine.
This volume is dedicated to one of the great educators and a leader in the pharmaceutical profession, August P. Lemberger, who is truly a Wisconsin man. At the University of Wisconsin in Madison, he was an undergraduate and graduate student.
He was then a professor, and twice Dean of the School of Pharmacy —44, —52, —69, — During the period between and , he assumed the responsibility of deanship at the University of Illinois, where I was a graduate student. In , he offered me my first teaching job, as an instructor of pharmacy at the University of Illinois, while I was still in graduate school. I was one of the greatest beneficiaries of his kindness and attention.
Gus has an unusual ability to put everyone at ease, respect everyone around him, and in the end, come out as a group leader. Whatever little I have accomplished in my life is mostly due to Gus.
Many awards, recognitions, and salutations were offered to Gus during his celebrated career. His research contributions included stability studies, suspension, emulsion stabilization, and later in his career, the various aspects of pharmaceutical education. I wish him many years of happy retirement and shuttling back and forth between his homes in Arizona and Wisconsin. Thanks, Gus. Pharmaceutical Scientist, Inc. Niazi has been teaching and conducting research in the pharmaceutical industry for over 30 years.
He has authored hundreds of scientific papers, textbooks, and presentations on the topics of pharmaceutical formulation, biopharmaceutics, and pharmacokinetics of drugs.
He is also an inventor with scores of patents and is licensed to practice law before the U. Patent and Trademark Office. Having formulated hundreds of products from consumer products to complex biotechnology-derived products, he has accumulated a wealth of knowledge in the science of formulations and regulatory filings of Investigational New Drugs INDs and New Drug Applications NDAs. Raw Materials Microbiological Quality Oral Suspensions Product Specifications