Handbook of Pharmaceutical manufacturing formulations second edition volume 1
The science
and the art of pharmaceutical formulation keeps evolving as new materials, methods, and
machines become readily available to produce more reliable, stable,
and release- controlled
formulations. At the same time, globalization of sourcing of raw and finished pharmaceuticals brings challenges to regulatory authorities and results in more frequent
revisions to the current good manufacturing practices, regulatory approval dossier
requirements, and the growing need
for cost optimization. Since the
publication of the first edition of
this book, a lot has changed in all of these areas of importance to
pharmaceutical manufacturers. The second edition builds on the dynamic nature of the science and art of formulations
and provides an evermore useful handbook that
should be highly welcomed by the industry, the regulatory authorities, as well as the teaching
institutions.
The first
edition of this book was a great
success as it
brought
under one umbrella the myriad of choices available to formulators. The readers were very responsive and communicated with me frequently pointing out to the
weaknesses as well as the strengths
of the book. The second edition totally revised
attempts to achieve these by making major changes to the text,
some of which include:
The science
and the art of pharmaceutical formulation keeps evolving as new materials, methods, and
machines become readily available to produce more reliable, stable,
and release- controlled
formulations. At the same time, globalization of sourcing of raw and finished pharmaceuticals brings challenges to regulatory authorities and results in more frequent
revisions to the current good manufacturing practices, regulatory approval dossier
requirements, and the growing need
for cost optimization. Since the
publication of the first edition of
this book, a lot has changed in all of these areas of importance to
pharmaceutical manufacturers. The second edition builds on the dynamic nature of the science and art of formulations
and provides an evermore useful handbook that
should be highly welcomed by the industry, the regulatory authorities, as well as the teaching
institutions.
The first
edition of this book was a great
success as it
brought
under one umbrella the myriad of choices available to formulators. The readers were very responsive and communicated with me frequently pointing out to the
weaknesses as well as the strengths
of the book. The second edition totally revised
attempts to achieve these by making major changes to the text,
some of which include:
1.
Complete, revised errors corrected and
subject matter reorganized for easy
reference. Whereas this series has six
volumes differentiated on the basis of the type of dosage form and a separate inclusion of the U.S. OTC products, ideally the entire collection is
needed to benefit from the myriad of topics relating to formulations, regulatory compliance, and dossier
preparation.
2. Total number of pages is increased
from 1684 to 2726.
3.
Total number of formulations is expanded by about 30% with many newly approved
formulations.
4.
Novel formulations are now provided for a
variety of drugs; these data are collected from the massive
intellectual property data and suggest toward the future trend of formulations. While some of these
formulations may not have been
approved in the United States or Europe, these
do provide additional choices, particularly for the NDA preparation. As always, it is the responsibility of the manufacturer to assure that the intellectual property rights are not violated.
A
significant change in this edition is the inclusion of commercial products; while most of this information is culled out from the open source such as the FOIA (http://www.fda.gov/foi/default.htm),
I have made at- tempts to reconstruct the critical portions
of it based on what I
call the generally acceptable standards. The
drug companies are advised to assure that any intellectual property
rights are not violated and this applies to all
information contained in this book. The freedom of information act (FOIA) is an extremely useful conduit for reliable information and manufacturers are strongly
urged to make use of this information. Whereas this in- formation is provided free of charge, the process of obtaining
the information may be cumbersome, in which case,
commercial sources of these databases can prove useful, particularly for the non-U.S.
companies.
5.
Also included are the new Good Manufacturing
Guide- lines (2007) with amendments (2008) for the United States and similar updates for European Union and WHO; it is strongly
urged that the companies discontinue using all
old documents as there are significant changes
in the re- vised form, and
many of them are likely to reduce the cost of GMP compliance.
6.
Details on design of clean rooms is a new
entry that will be of great use to sterile
product manufacturers; whereas
the design and flow of personnel and material flow is of critical nature, regulatory agencies
view these differently and the manufacturer is advised always to comply with most stringent requirements.
7.
Addition of a self-auditing template in each
volume of the series. While the cGMP
compliance is a complex is sue
and the requirements diversified across the globe, the basic compliance remains universal. I have chosen the European Union guidelines (as these are
more in tune with the ICH) to prepare
a self-audit module that I recommend that every manufacturer adopt as a routine
to assure GMP compliance. In most
instances reading the template by
those responsible for compliance with keep them sensitive
to the needs of GMP.
8.
OTC products cross-referenced in other
volumes where appropriate. This was necessary since the regulatory authorities worldwide define this class of drug differently. It is important to iterate that
regardless of the prescription or the OTC status
of a product, the requirements for compliance with the cGMP apply equally.
9.
OTC monograph status is a
new section added to the OTC volume and this should allow manufacturers to chose ap- propriate formulations that may not require a filing with
the regulatory agencies; it is important to iterate that an approved OTC monograph includes details
of formulation including the types and
quantities of active drug and excipients,
labeling, and presentation. To qualify the ex-
emption, the manufacturer must comply with the mono- graph in its entirety. However, subtle modifications that are merely
cosmetic in nature and where there is an evidence that the modification will not affect the safety and efficacy of the products can be made but
require prior approval of the regulatory
agencies and generally these approvals are granted.
10. Expanded discussion
on critical factors in the manufacturing of formulations provided; from basic shortcuts to smart modifications now extend to all dosage forms. Pharmaceutical compounding is one of the
oldest professions and whereas
the art of formulations has been
relegated to more objective parameters, the art nevertheless remains. An
experienced formulator, like an artist, would know what goes with what and why;
he avoids the pitfalls and stays with conservative choices. These sections of
the book present advice that is time tested, although it may appear random at
times; this is intended for experienced formulators.
11. Expanded
details on critical steps in the manufacturing processes provided but to keep
the size of the book man- ageable, and these are included for prototype formulations.
The reader is advised to browse through similar formulations to gain more
insight. Where multiple formulations are provided for the same drug, it
intended to show the variety of possibilities in formulating a drug and whereas
it pertains to a single drug, the basic formulation practices can be extended
to many drugs of same class or even of diversified classes. Readers have often
requested that more details be provided in the Manufacturing Direction
sections. Whereas sufficient details are provided, this is restricted to
prototype formulations to keep the size of the book manageable and to reduce redundancy.
12. Addition
of a listing of approved excipients and the level
13. allowed
by regulatory authorities. This new section al- lows formulators a clear choice
on which excipients to choose; the excipients are reported in each volume pertaining
to the formulation type covered. The listing is drawn from the FDA-approved
entities. For the developers of an ANDA, it is critical that the level of
excipients be kept within the range generally approved to avoid large expense
in justifying any unapproved level. The only category for which the listing is
not provided separately is the OTC volume since it contains many dosage forms
and the reader is referred to dosage form–specific title of the series. The
choice of excipients forms keeps increasing with many new choices that can
provide many special release characteristics to the dosage forms. Choosing correct
excipients is thus a tedious exercise and requires sophisticated multivariate
statistical analysis. Whereas the formulator may choose any number of novel or
classical components, it is important to know the levels of excipients that are
generally allowed in various formulations to reduce the cost of redundant
exercises; I have there- fore included, as an appendix to each volume, a list
of all excipients that are currently approved by the U.S. FDA along their
appropriate levels. I suggest that a formula- tor consult this table before
deciding on which level of excipient to use; it does not mean that the
excipient cannot be used outside this range but it obviates the need for a
validation and lengthy justification studies in the submission of NDAs.
14. Expanded
section on bioequivalence submission was
required
to highlight the recent changes in these requirements. New entries include a comprehensive
listing of bioequivalence protocols in abbreviated form as ap- proved by the
U.S. FDA; these descriptions are provided in each volume where pertinent. To
receive approval for an ANDA, an applicant must generally demonstrate, among
other things, equivalence of the active ingredient, dosage form, strength,
route of administration and conditions of use as the listed drug, and that the
pro- posed drug product is bioequivalent to the reference listed drug [21 USC
355(j)(2)(A); 21 CFR 314.94(a)]. Bioequivalent drug products show no
significant difference in the rate and extent of absorption of the therapeutic ingre dient [21 U.S.C. 355(j)(8); 21 CFR 320.1(e)]. BE studies are undertaken
in support of ANDA submissions with the goal
of demonstrating BE between a proposed generic
drug product and its reference listed drug. The regulations governing BE are provided
at 21 CFR in part
320.
The U.S. FDA has recently begun to promulgate
individual bioequivalence requirements. To streamline the process for making guidance
available to the pub lic on how to design
product-specific BE studies,
the
U.S. FDA will be issuing product-specific BE recommend dations
(www.fda.gov/cder/ogd/index.htm).
To make this vital information available, an appendix to each volume includes a summary of all
currently approved products by the
U.S. FDA where a recommendation on conducting
bioequivalence studies is made available by
the U.S. FDA. When filing an NDA or an ANDA, the filer is faced with the choice of defending the methods
used to justify the bioavailability or bioequivalence data. The U.S. FDA now allows application for waiver of bioequivalence requirement; a new
chapter on this topic has been added along with details of the dis- solution
tests, where applicable, approved for various
dosage forms.
15.
Dissolution
testing requirements are included for all
dosage
forms where this testing is required by the FDA. Surrogate testing to prove efficacy and compliance is get- ting
more acceptance at regulatory agencies;
in my expe rience, a
well-designed dissolution test is the best measure of continuous compliance.
Coupled with chapters on waivers
of bioequivalence testing,
this information on dissolution
testing should be great value to all manufacturers; it is recommended that manufacturers develop
their own in-house specifications, more stringent than those allowed in these listings
and the USP.
16.
Best-selling
products (top 200 prescription products)
are identified with an
asterisk and a brand name where applicable; in
all instances, composition of these products is provided and formulation of generic equivalents. Despite the vast expansion of
pharmaceutical sales and shifting of
categories of blockbuster drugs, basic drugs affecting gastrointestinal tract, vascular system, and brain remain most widely prescribed.
17.
Updated list of approved coloring agents in
the United States, Canada, European
Union, and Japan is included to allow manufactures to design products
for worldwide distribution.
18.
Tablet-coating formulations that meet worldwide re quirements of color selection
are included in the Volume
1 (compressed solids) and Volume 5 (OTC) because these represent the products often coated.
19.
Guidelines on preparing regulatory filings
are now dispersed throughout the series depending on where these guidelines are more crucial.
However, the reader
would, as before, need access
to all volumes to benefit from the advice and guidelines provided.
