Handbook of Pharmaceutical Manufacturing Formulations - Over-the-Counter Products (Volume 5 of 6)

350 Pages·2004·5.465 MB·English

by  Sarfaraz K Niazi

H A N D B O O K O F
Pharmaceutical
Manufacturing
Formulations
Over-the-Counter Products
V O L U M E 5
© 2004 by CRC Press LLC
Handbook of
Pharmaceutical Manufacturing Formulations
Volume Series
Sarfaraz K. Niazi
Volume 1
Handbook of Pharmaceutical Manufacturing Formulations:
Compressed Solid Products
Volume 2
Handbook of Pharmaceutical Manufacturing Formulations:
Uncompressed Solid Products
Volume 3
Handbook of Pharmaceutical Manufacturing Formulations:
Liquid Products
Volume 4
Handbook of Pharmaceutical Manufacturing Formulations:
Semisolid Products
Volume 5
Handbook of Pharmaceutical Manufacturing Formulations:
V O L U M E 1
Over-the-Counter Products
Volume 6
Handbook of Pharmaceutical Manufacturing Formulations:
Sterile Products
© 2004 by CRC Press LLC
H A N D B O O K O F
Pharmaceutical
Manufacturing
Formulations
Over-the-Counter Products
V O L U M E 5
Sarfaraz K. Niazi
CRC PR ESS
Boca Raton London New York Washington, D.C.
© 2004 by CRC Press LLC
Library of Congress Cataloging-in-Publication Data
Niazi, Sarfaraz, 1949–
Handbook of pharmaceutical manufacturing formulations / Sarfaraz K. Niazi.
p. cm.
Includes index.
Contents: — v.5. Over-the-Counter Products
ISBN 0-8493-1750-9 (alk. paper)
1. Drugs—Dosage forms—Handbooks, manuals, etc. I. Title
RS200.N53 2004
615'19—dc21
2003051451
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Printed in the United States of America 1 2 3 4 5 6 7 8 9 0
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© 2004 by CRC Press LLC
Dedication
Dedicated to the memory of Dean Allen I. White
© 2004 by CRC Press LLC
Preface to the Series
No industry in the world is more highly regulated than products. Sterile products require skills related to steril-
the pharmaceutical industry because of the potential threat ization of the product; of less importance is the bioavail-
to a patient’s life from the use of pharmaceutical products. ability issue, which is an inherent problem of compressed
The cost of taking a new chemical entity to final regulatory dosage forms. These types of considerations have led to
approval is a staggering $800 million, making the phar- the classification of pharmaceutical products into these six
maceutical industry one of the most research-intensive categories. Each volume includes a description of regula-
industries in the world. It is anticipated that the industry tory filing techniques for the formulations described. Also
will spend about $20 billion on research and development included are regulatory guidelines on complying with Cur-
in 2004. Because patent protection on a number of drugs rent Good Manufacturing Practices (cGMPs) specific to
is expiring, the generic drug market is becoming one of the dosage form and advice is offered on how to scale-up
the fastest growing segments of the pharmaceutical indus- the production batches.
try with every major multinational company having a sig- It is expected that formulation scientists will use this
nificant presence in this field. information to benchmark their internal development pro-
Many stages of new drug development are inherently tocols and reduce the time required to file by adopting
constrained by time, but the formulation of drugs into formulae that have survived the test of time. Many of us
desirable dosage forms remains an area where expediency who have worked in the pharmaceutical industry suffer
can be practiced by those who have mastered the skills of from a fixed paradigm when it comes to selecting formu-
pharmaceutical formulations. The Handbook of Pharma- lations: “Not invented here” perhaps is kept in the back
ceutical Manufacturing Formulations is the first major of the minds of many seasoned formulations scientists
attempt to consolidate the available knowledge about for- when they prefer certain platforms for development. It is
mulations into a comprehensive and, by nature, rather expected that with a quick review of the formulation pos-
voluminous presentation. sibilities that are made available in this book such scien-
The book is divided into six volumes based strictly on tists would benefit from the experience of others. For
the type of formulation science involved in the develop- teachers of formulation sciences this series offers a wealth
ment of these dosage forms: sterile products, compressed of information. Whether it is selection of a preservative
solids, uncompressed solids, liquid products, semisolid system or the choice of a disintegrant, the series offers
products, and over-the-counter (OTC) products. Although many choices to study and consider.
they may easily fall into one of the other five categories,
OTC products are considered separately to comply with Sarfaraz K. Niazi, Ph.D.
the industry norms of separate research divisions for OTC Deerfield, Illinois
© 2004 by CRC Press LLC
Preface to the Volume
The Handbook of Pharmaceutical Manufacturing Formu- that this category of products is now under U.S. FDA
lations: Over-the-Counter Products is written for the phar- watch. Often years go by before Proposed Rules are pub-
maceutical scientist and others involved in the regulatory lished in the Code of Federal Regulations. The Proposed
filing and manufacturing of new OTC products. Because Rules include not only identification of approved active
of the wide variety of products involved, from those bor- ingredients but also inactive ingredients that are deemed
dering on cosmetics to proton pump inhibitors, the OTC compatible with the active ingredients and safe for con-
products are manufactured by the most sophisticated glo- sumers. The Proposed Rules are subject to criticism by
bal manufacturers as well as small one-room makeshift the industry healthcare practitioners and consumers. After
manufacturing houses. receiving these comments over what can be a period of
The OTC products comprise a special category of several years, the U.S. FDA issues Final Rules on a spe-
healthcare products in that they can be dispensed without cific category of products; these become official on the
prescription, the rationale being that the use of these prod- date of publication in the Code of Federal Regulations. In
ucts does not expose patients to serious risks associated many cases, however, the U.S. FDA issues subsequent
with side effects even if some misuse or overuse of these rules either to delay application of Final Rules or to mod-
products occurs. The OTC category includes three types ify the Final Rules if new information has become avail-
of products: able.
The Final Rule requirements have primarily been
• Products that require full filing with the U.S. applied to products on the market and a newcomer is well
Food and Drug Administration (FDA) for mar- advised to study competitor products for market leaders
keting approval (the NDA/NADA or as ample opportunities are available to innovate these
aNDA/aNADA process) including products or products. Examples include the Tylenol® Hot Therapy
compositions not included in the monographs products and loratidine tablets that dissolve in the mouth
(see below) or administered in controlled and do not require water. I foresee more such products
release formulations entering into the ever-competitive OTC market.
• Products that do not require filing with the U.S. It is imperative that any prospective entry into the OTC
FDA because they comply with the monographs market should begin with a thorough consultation of the
issued by the U.S. FDA in its Code of Federal Final Rules; an examination of Proposed Rules and noti-
Regulations (CFR) fications to issue Proposed Rules is also helpful in deter-
• Products that fall under the category of grand- mining what rules are about to become Final Rules.
father products which have been in use prior to Reviewing the discussions about Proposed Rules that have
the 1960s and have not been specifically affected their finalization can be very helpful in under-
excluded by the FDA; not all grandfather prod- standing the relevant issues of safety, efficacy and label-
ucts fall under the OTC category — only those ing. Because the marketing of OTC products requires a
that are Generally Regarded As Safe (GRAS) large investment in marketing efforts, it is prudent to
develop a clear understanding of the legality of formula-
The U.S. FDA provides excellent support through its OTC tions and claims made in the initial phases of product
website (http://www.fda.gov/cder/otc/index.htm) and for- development.
mulators are highly encouraged to make use of the infor- A large number of products on the market today are
mation available, particularly the updates in the mono- not covered by the U.S. FDA monographs but does that
graph label requirements and withdrawal of approvals of make them legitimate? This is the often-asked question.
formulations. The U.S. FDA has limited resources to tackle everything
With the safety of consumers in mind, the U.S. FDA that is out there on the market. When emergencies arise,
is in the process of establishing guidelines for all OTC however, the U.S. FDA reacts immediately as it did in the
products. Although the U.S. FDA began this work over case of phenylpropanolamine, pseudoephedrine and
three decades ago, much remains to be done. The U.S. recently, kava kava. Here are some broad guidelines
FDA process begins with the issuance of Proposed Rules; adopted by the U.S. FDA for the most commonly abused
this notification is like a warning (or advice) to the industry categories of products:
© 2004 by CRC Press LLC
1. No treatments are approved for hair growth gastrointestinal symptoms which although temporary
except for minoxidil. were sufficient to disallow the status switch. Obviously
2. No treatments are approved for enhancing sex- Roche would have been best advised to develop an OTC
ual performance except for sildenafil citrate formulation with fewer side effects before requesting this
(and that only in MED). switch. (In the case of orlistat, the solution was simple as
3. The few treatments approved for weight loss described in U.S. Patent No. 6,251,421 by this author
include olristat phentermine and sibutramine wherein combining orlistat with a natural fiber reduced
(phenylpropanolamine is no longer a recom- the side effects by 70%.)
mended compound). The OTC category of products represents a wide range
of dosage forms. These formulations have much in com-
It is noteworthy that the U.S. FDA does not differentiate mon with their prescription counterparts but are presented
between botanical products and chemical-based products. in this volume of the Handbook of Pharmaceutical Man-
If a product bears an efficacy claim it must be governed ufacturing Formulations because of the development
by U.S. FDA rules; however a product that falls into a approach taken, labeling considerations, and support
drug category that makes nutritional claims falls under a available from suppliers of ingredients in designing these
food category with its own set of detailed rules. Vitamins products. Because the consumer is inevitably involved in
and minerals fall under food labeling guidelines; however the selection of these products, packaging considerations
a single-entity vitamin product with specific claims to treat are much more important than in the prescription category
or ameliorate a disease is a drug product. These definitions of products. Additional considerations include ease of
do not necessarily coincide with the rulings of regulatory administration, palatability, and stability in storage as con-
authorities worldwide. In many countries nutritional prod- sumers are likely to keep leftovers around for a long time.
ucts are controlled as drugs and require prescriptions; Additionally, price constraints often make it difficult to
these same products would be considered non-prescription enjoy some freedom of choice in formulations especially
items in the United States. On the other hand a number if the innovator company faces the competition of house
of highly active drugs are available without prescription brands. All of these considerations taken together make
in many countries such as the Traditional Chinese Medi- the OTC category one that should be presented in a single
cine (TCM) in China and Ayurvedic and Unani medicines volume of this series of books.
in South Asia. Formulating OTC products is generally easier than
A reclassification of a drug to OTC status can be formulating prescription products if the product is
requested by drug manufacturers. Recent examples of described in U.S. FDA monographs (either as Proposed
such a prescription-to-OTC switch include ibuprofen (200 Rules or Final Rules); such formulations become merely
mg), ranitidine hydrochloride (75 mg), and loratidine (10 an exercise in mechanics. Whereas a manufacturer is not
mg). Note that specific strengths, not necessarily the bound by these rules, complying with them reduces the
chemical entity itself, are made OTC. In other words it is costs and time involved securing approval from regulatory
not necessary to have an official monograph to secure OTC authorities. The multibillion-dollar market of OTC prod-
status for a drug. The decision to request reclassification ucts has attracted major chemical suppliers to develop
of a drug as OTC is always a well-calculated business support ingredients that are much easier to use; they have
decision. Generally drugs with an OTC status will not also developed typical formulations for hundreds of these
qualify for medical reimbursement by insurance compa- products.
nies or federal assistance programs in the United States. The most notable industry leaders include:
This can substantially reduce sales of the product; on the
other hand, ease of availability to a greater number of • Amerchol
patients can easily compensate for this loss. The most • American Colloid
lucrative opportunities arise when one strength is made • Aqualon
OTC while other strengths remain available by prescrip- • BASF
tion only. • BF Goodrich
It is noteworthy that the decision to allow a switch from • Calgon
prescription to OTC by the U.S. FDA is primarily driven by • Colorcon
the side effects or toxicity of the drug. For example, in • Croda
Australia a Roche request for a prescription-to-OTC switch • Dow Corning
for its weight-loss drug orlistat (Xenical®) was recently • FMC
turned down because of extensive side effects associated • Gattefose
with the use of Xenical. The drug itself is very safe as it • General Electric
does not enter the body and acts only locally to partially • Henkel
block absorption of fat. The unabsorbed fat produces many • Hormel
© 2004 by CRC Press LLC
• Huls America Stability considerations remain paramount, and the
• ICI Americas data in the final packaging must be evaluated carefully
• Inolex before adjusting formulae for excesses; in this book, most
• International Sourcing formulations are provided without this consideration. A
• International Specialty strip or blister dosage form is more popular around the
• Laboratoires Serobioligique world, but the plastic bottle is the most popular final form
• Lonza in the United States.
• NIPA The development of OTC products is similar to the
• PPG Industries development of prescription dosage forms; as a result,
• R.I.T.A. cGMP and Good Laboratory Practice (GLP) consider-
• Reheis ations apply equally. The first chapter describes in greater
• Rheox detail the cGMP considerations. An Appendix to Chapter
• Rhone-Poulenc 1 provides a comprehensive checklist of items to review
• Rohm and Haas to ensure that a manufacturing facility is in compliance
• Southern Clay with cGMP standards. Appropriate identification is made
• Sutton in this checklist of those items that comply with EC guide-
• Vanderbilt lines. The U.S. FDA guidelines are available from the U.S.
FDA website: http://www.fda.gov. The World Health
The formulations recommended by these and other com- Organization (WHO) provides GMP guidelines that are
panies have acquired almost a universal appeal; through- less stringent than those of the U.S. FDA and EC, and
out this book you will find formulations recommended by formulators should be aware of the fact that all of these
these laboratories, as acknowledged by the listing of a are simply guidelines. One should be fully cognizant of
brand name in the formula. The best way to connect to the fact that no agencies are bound by these guidelines,
these companies is to search the Internet for contact infor- particularly the U.S. FDA. Manufacturers cannot take ref-
mation; it is no longer necessary to reproduce such infor- uge in the defense that they have complied with these
mation here. Whereas many companies prefer to use guidelines. It is further worthwhile remembering that all
generic components in the dosage form, it has been found of these guidelines are continuously revised, and the “c”
that the use of proprietary components can indeed reduce in the cGMP does refer to current.
costs in the long run. The second chapter deals with the most popular cat-
The choice of color is a highly sensitive issue in the egory of dosage forms encountered in OTC offerings —
formulation of OTC products; only FD&C colors are solids. Issues specific to manufacturing of these dosage
allowed. Whereas there is a great need to make the prod- forms are described from a practical viewpoint, indicating
ucts attractive and appealing, the choices of safe colors the problem areas frequently encountered in manufactur-
are dwindling quickly, such as for red colors. The formu- ing practice.
lator is encouraged to review the status of approved colors The third chapter deals with liquids and suspensions
around the world before committing to a specific color. and includes, like the chapter above, practical advice on
Many OTC solid dosage forms are available in coated how to bring manufacturing practices into compliance
form. Sugar coatings have yielded to film coatings, and with regulatory requirements.
this book contains a large number of sugar-coating, seal- The fourth chapter offers highlights of cleaning vali-
coating, subcoating, film-coating, and polish-coating for- dation, a topic often ignored by OTC manufacturers as not
mulations that can be easily adapted to various dosage being significant because of the safety of ingredients used.
form sizes. The use of organic solvent-based coatings has It is true that the same stringent standards may not apply,
become prohibitive because of environment consider- but compliance with cleaning standards and validation of
ations, but in those cases where formulations are processes go a long way toward ensuring overall compli-
extremely sensitive to moisture, organic coatings may still ance.
offer a valid choice. A few companies offer ready-made The first four chapters were drawn from advice the
coating formulations, and these are worth considering. U.S. FDA gives to its inspectors before they inspect a
The Appendix to this book includes a large number of manufacturer. The CFR includes complete details of what
formulations of coatings of solid dosage forms. A keen is considered acceptable by the U.S. FDA; this advice is
formulator will have no difficulty based on these formu- of a practical nature, and I find it to be extremely helpful
lations in adopting a coating system that will provide the in enhancing awareness of the guidelines of regulatory
necessary protection and offer esthetic appeal as well. authorities. It is noteworthy that EC guidelines, particu-
Solid dosage forms are coated for many reasons, including larly in light of the harmonization of specifications, are
masking the taste, making them easier to swallow, and somewhat identical to the U.S. FDA guidelines; in chapter
providing protection against the environment. 1, specific references are made to EC guidelines. The
© 2004 by CRC Press LLC
Appendix includes formulations of coating solutions; http://www.pharmsci.com. Because of the wide variety of
these should prove useful for the pharmaceutical formu- sources from which the information has been gathered in
lation teams. the book, the format of formulations also varies. For exam-
The formulations in this book generally fall into three ple, in some instances scale is provided, whereas in others
categories. Some formulations are presented in greater a percentage by weight is described. In still other
detail, including indications of where quality assurance
instances, quantities for a specific batch size are provided.
(QA)/quality control (QC) sampling is to be done and
Obviously, it would be desirable to convert these formu-
describing the tooling and in-process and finished product
lations into a uniform format, but the task would be daunt-
specifications. The other extreme is a mere listing of com-
ing and inevitably would lead to inclusion of errors. Pro-
ponents with a bare minimum of manufacturing methods.
fessional formulators should not encounter any difficulty
This was necessary for two reasons: first, to contain the
in adapting these formulations to their own system.
size of this book, and, second, to keep from presenting
As mentioned before, not all formulations contain the
superfluous information, as formulators would eventually
required overages for stability considerations and losses
adopt such a formula to their own delivery forms. Also,
during manufacturing; formulators are expected to
at times the various strengths are merely achieved through
develop these based on the final packaging chosen for the
adjustment of dosage size, so it was considered unneces-
product. The author would appreciate being notified of
sary to reproduce manufacturing steps where they are
obvious. any special problems encountered in adopting these for-
The primary source of these formulations is publicly mulations or of any errors ([email protected]). Whereas
available knowledge about formulae that have proven to much care has gone into ensuring the accuracy of quan-
provide stable products. No representation is made that these tities and proper identification of ingredients, such errors
formulations meet U.S. FDA monographs or any other reg- shall remain in a work as large as that presented here.
ulatory guidelines for safety of inert ingredients. The formu-
lator is advised to determine guideline compliance before Sarfaraz K. Niazi, Ph.D.
adopting any of the formulations given in this book. Those Pharmaceutical Scientist, Inc.
interested in obtaining detailed information about these 20 Riverside Drive
formulations are encouraged to contact the author at Deerfield, Illinois 60015
© 2004 by CRC Press LLC