International Journal of Generic Drugs

International Journal Volume 03 2000

Generic20@&?00Drugs N u m b e r 08
Drug Development & Manufacture for Pharmaceutical Research Scientists

Features reviews and articles on Drug

Development for the Pharmaceutical
R&D, RA, QA and Manufacturing
Scientist.

• Generic & Innovative Drug

Development. - Formulations

• Bioequivalency - IVIVC - CDPs

• Quality Control /Assurance

• PAI Know How

generic • Microbiology Control

• Pharmaceutical Stability

• Regulatory Affairs
• Global Product Registration

• Bulk Pharmaceutical Chemical

drugs
International Journal of Generic Drugs
GMP/validation

• Features the Ins-and-Outs of NDA

CMC Sections
• Generic Drug Manufacturing
Development and Manufacture of
Generics and NDA CMC sections • New Assays & Impurity Profiles
for the Pharmaceutical
Scientist.

LOCUM Publishing House

International Journal of Generic Drugs

ISSN 0793 694X US/Canada ISSN 0793-7784 Euro ISSN 0793-7822 Pacific Rim.
 International Journal of Generic Drugs

Ó 20&
&00Î
Î ♦ Quality Control and Assurance
◊ Audits and vendor inspections
International ◊ Vendor audits by mail/fax

♦ Microbiological Controls
Journal of ◊ Purified Water USP - when to use it
◊ Topicals and their controls
Generic Drugs ◊ Cleaning Limits
Electronic < Journal on Disk ♦ Pharmaceutical Stability
Journal on : the Web ◊
◊
Auditing your Stability Department
Time limitations in the stability protocols
◊ Checking the Reference Listed Drug
e-- Journal ◊ Reduced Testing Plans - Bracketing / Matrixing

♦ Analytical Aspects
ISSN 0793 694X ; 0793 7784 ; 0793 7822

◊ Auditing Raw Data / Impurities / Limits

T A B L E O F C O N T E N T S ◊ Handling graphs and print-outs
2000- 2001 Issues ◊ High Speed stability assay validations
◊ Model validation protocols /Assay /Dissolution
(Representative list of the current 2000
◊ Residual Solvents, OVI's & Limits/Regulations
Table of Contents in Summary Form) ◊ Ruggedness and Robustness / FDA vs.ICH

♦ Material Selection ♦ Auditing your firm

◊ Spotting Deficiencies before PAI inspections
◊ Choosing the right active
◊ Building in success for PAIs & File Reviews
◊ Choosing the right excipient
◊ Choosing the right dyes and colors ♦ Regulatory Affairs
◊ DMF's - Do's and Don'ts ◊ ANDA & Global Generic Development
◊ Global Product Registration made simple
◊ The Development Notebook
◊ ANDA Templates for any Documentation System
♦ Generic Drug Manufacture ◊ All ANDAs made simple / EU interfacing
◊ Preparing the right documentation ♦ Regulatory Do’s and Don’ts
◊ Manufacturing Instructions Do’s and Don’ts ◊ Tips and traps to consider
◊ Developing the Formula from A - Z ◊ Annual Reports made simple
◊ Developing CR / MR/ ER and DR forms
♦ Bulk Pharmaceutical Chemicals
◊ Development Checklist Step - by - Step. ◊ Actives for Generic Drugs
◊ Individual and Population Bioequivalence ◊ Drug Master Files - Actives
◊ Bioequivalence and IVIVC, & CDP's ◊ How and What to Validate
♦ Setting the correct specifications ♦ New Regulations
◊ In-process, Release and Check Specifications ◊ Bioequivalent Food/Fasting Studies, BCS, Waivers
◊ Decision trees (Polymorphism, Impurities etc.) ◊ How to handle New OGD's Regulations.
◊ 10 key Decision Trees in SOPs ◊ OGD Regulations Made Simple
◊
♦ Process validation and protocols Converting FDA speak into Plain English

◊ Scale-up for specific dosage forms ♦ Current Checklists

◊ Cleaning validation requirements ◊ Generic Development Checklists
◊ PAIs and Post approval Inspections ◊ Analytical checklists, Protocols, Validation
◊ Tablet Hardness Qualification / LOD ◊ Stability Indicating System checklists
◊ Sampling and Testing the Pivotal Batch ◊ PAI Approvals - All that's necessary
◊ Drug Development Checklist - Solid Oral Dosages
♦ Container-closure Systems ◊ Drug Development Checklist - Liquid & Suspensions
◊ Closure DMF's - vendors obligations
◊ ANDA container-closure requirements ♦ SOPs of the Month
◊ New SOPs for generic firms
◊ EC and ANDA comparisons
◊ Ten Major Decision Trees
◊ Getting the paper work right-first time
◊ Current SOPs you should have
◊ New guidelines / New DMF obligations ◊ SOPs for your firms security.
◊ USP / 21 CFR / Indirect Food Regulations
♦ Regulatory and Patents Info
♦ Biostudies ◊ The Generic Drug Enforcement Act
◊ Food/Fasting Studies, BCS, Waivers ◊ Seminar/Conference Summaries
◊ ABE, IBE, IVIVC, CDP Bio Conferences ◊ Drugs Off-Patents to the year 2016
◊ Drugs coming Off-Patent (annually).
International Journal of Generic Drugs
ISSN 0793 694X US/Canada ISSN 0793-7784 Euro ISSN 0793-7822 Pacific Rim
 International Journal of Generic Drugs

International Journal of G eneric D rugs

OFFICIAL PUBLICATION OF THE INTERNATIONAL ASSOCIATION OF DRUG MANUFACTURERS

E D I T O R I A L
E D I T O R - I N - C H I E F
J E R E M Y D B L O C K

The International Journal of Generic Drugs publishes articles reviews and papers on all aspects
of Generic and Innovative Drug Development from pre-formulation to aspects of regulatory
strategy. Emphasis is placed on the US and EU exposure of the Generic Drug Industry with
special reference to the on-time development of ANDA / EU submissions. The Chemistry,
Manufacture and Controls (CMC) section of NDA development cover hands-on nuts-and-bolts
developmental issues that vary across the full drug development spectrum from documentation
requirements, excipients specifications, development (pre-to-final) formulation, scale-up,
analytical, cleaning and process validation protocols necessary for the entire drug development
process. The overall objective in generic / CMC drug development is to get the newly developed
product to the market place on time. The Journal attempts to clarify and simplify development and
regulatory issues to achieve this crucial objective, as a major and vital IT provider .
Articles include pre-formulation; drug development; granule sampling; bioequivalence data;
specific container closure aspects, and manufacturing techniques; Quality Control; Quality
Assurance; comprehensive development analytical assay and impurity methodology via IAGIM,
pharmaceutical stability in conjunction with regulatory requirements and model Abbreviated New
Drug Applications. Three differing geographic editions (US & Canada; Euro; Pacific Rim) are
published highlighting various technological interests specific to each area.
The Journal publishes Drugs-Off-Patent™ Special Reports up to the year 2016 including Currents Drugs
in Today's Pipeline and holds updated lists and evaluation reports of Waxman/Gatt Patent/ Exclusivity
Extensions for the coming 15/17 years. The Journal reviews issues that impact on all pivotal aspects of
drug approval system with specific details for ANDA/AADAs NDAs and EU Dossiers including
international perspectives on regulatory affairs. Features unique, authoritative side-by-side
comparisons, summaries and development drug checklists as a Journal specialty.
The International Journal of Generic Drugs provides a free exchange of scientific knowledge while
promoting the generic and innovative pharmaceutical sciences. Selected papers, articles and reviews
may be compiled by the publishers and incorporated after editing into the 24 volume authoritative
Handbooks of Pharmaceutical Generic Drug Development™ series with each volume, (updated
twice annually), targeting in full details a specific dosage form. Reviews and papers are refereed, while
scientific correspondence is subject to editorial oversight. Contributions to this Journal are
published free of charge. The Journal is printed on acid-free paper (up to 60% recycle content)
meeting ISO 9706, SFS 1083 and Nordic Environmental Standards of Certification. 4
The International Journal of Generic Drugs and Journal of Drug Development are the Official Journals of the
International Association of Generic and Innovative Drug Manufacturers. Annual subscriptions rates for this Journal
to non-members is US $285. Institutional rate is $330 by Air mail (Reduced rates are available to accredited
members of the International Association of Generic and Innovative Drug Manufacturers - I.A.G.I.M. at $265 Print
and $100 for the Electronic Edition) The Electronic Journal is available on disk, Locum Journal Navigator and
subscribers of the Electronic International Journal of Generic Drugs (US $195) may have their subscription
transmitted to their e-mail addresses. The subscription for Electronic multiple-users in large firms, universities or
similar affiliations is $330. Electronic back order issues are $42 each (Print $48) The International Journal of
Generic Drugs may be reviewed via the World Wide Web where the public may download a web-edition Journal in
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International Journal of Generic Drugs

 International Journal of Generic Drugs

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ISSN 0793 694X US/Canada ISSN 0793 7784 Euro ISSN 0793 7822 Pacific Rim
 International Journal of Generic Drugs

A Word from Our Publishers

International
Jo u r n a l o f T he International Journal of Generic
Drugs is a leading pharmaceutical
scientific journal. Peer reviewed by the
Editorial Advisory Board, the journal offers
Generic Drugs a regular subscription via print, electronic
ISSN 0793 694X - ISSN 0793 7784 - ISSN 0793 7822 diskette, Online or e-mail distribution.
The journal is distributed in three
Electronic < Journal on Disk geographic world zones. US/Canada

Journal on : the Web

issues - start at calendar year, Euro
issues - start at mid-year and Pacific Rim
e-- Journal issues - start at the academic year.
ISSN 0793 7415
Electronic < J ournal- o n -Disk
The International Journal of Generic The Electronic International Journal of
Drugs is published every six to eight Generic Drugs is available on 3.5 Disk in
weeks in print and electronic formats. Adobe’s Portable Document Format
Journal statistics:- The International (PDF™). The Acrobat Reader is a free
reader and is available via our web sites
Journal of Generic Drugs distribution
linked direct to Adobe's site.
stands at approximately +1900 to
Full Yearly Volumes are available on CD.
Universities, Institutional Organizations,
A complementary e-Journal may be
Pharmaceutical Consultants, Generic
requested via email (as an attachment).
Drug firms, and research-based
pharmaceutical firms. J ournal on : the Web
The Journal is distributed to over thirty The Electronic Web version of the
five Regulatory Agencies in the Canada, International Journal of Generic Drugs
Chile, China, European Union Countries may be reviewed or down loaded from
(18), India, Taiwan, Japan, US, and the any of the publishers' web sites at:-
majority of the Pacific Rim countries. - www. l o c u m . c o . i l
- www. l o c u m U S A . c o m
- www. l o c u m E u r o . c o m
SATISFACTION GUARANTEED - www. l o c u m P a c i f i c . c o m (2000)
• If you do not learn practical, hand-on,
nuts and bolts, time saving tactics,
e- - Journal
saving thousands of development dollars The Electronic International Journal of
and have a better idea on how to avoid Generic Drugs is transmitted via the
FDA and OGD pitfalls and file deficiency Internet to the subscriber’s own e--
challenges. address. This is faster to download than
Our policy is to satisfy every customer. reviewing the ONLINE edition.
We offer a 60 day risk free guarantee. Complimentary e-mail issues are sent
If you are not completely satisfied with each month to international agency
the technology we will gladly issue a regulators and government departments.
credit for the full price paid - and the
Journals received are yours to keep. The & Journal
The International Journal of Generic
• That’s our no-risk full credit guarantee Drugs printed edition is posted every six
--- weeks to the subscriber's specified
Applicable only where special discounts or free
advertising has not been claimed. mailing address. (8 per annum, plus
special supplements to IAGIM members).

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ISSN 0793 694X US/Canada ISSN 0793 7784 Euro ISSN 0793 7822 Pacific Rim
 International Journal of Generic Drugs

International
Jo u r n a l o f Editorial
Generic Drugs 19Calendar99
ISSN 0793 7784 Vol. 03 - No 01
Electronic < Journal on Disk Ad Closing:
Materials:
5 May. 1999
8 May. 1999
Journal on : on Web Publishes: 30 May 1999

e-- Journal
Vol. 03 - No 02
ISSN 0793 7806 Ad Closing: 13 June 1999
Ï 19v99Ò Materials: 18 June 1999
Publishes: 9 July 1999
Editorial and Publishing Staff
Ó 19v99Î Vol. 03 - No 03
Chief Executive Officer Monica A. Graham Ad Closing: 12 August 1999
v
Materials: 19 August 1999
Editor-in-Chief Jeremy D. Block
v Publishes: 25 August 1999

Vol. 03 - No 04
Managing Editor Jenny A . Slement
v
Group Editor Robert C. Ford
v Ad Closing: 4 Sept 1999
Marketing Service Editor Brian O' Keeffe Materials: 8 Sept 1999
v Publishes: 25 Sept 1999
Associated Editor Caroline Frost
Associated Editor
v
Mary Leddingham
Vol. 03 - No 05
Director of Administration Dori Belle Ad Closing: 5 Oct. 1999
v
Materials: 10 Oct. 1999
Senior Scientific Editor Pat West
v Publishes: 25 Oct. 1999

Vol. 03 - No 06
Director of Operations David Sydney
v
Financial Manager Edanna Holman
v Ad Closing: 01 Nov. 1999
Editorial Assistants Sue Bailey-Wood Materials: 06 Nov. 1999
v Publishes: 12 Nov. 1999

Vol. 03 - No 07
Circulation & Graphic Manager Ari Jonathan
v
Electronic Archivist Charles Taylor-Evans
v Ad Closing: 5 Dec. 1999
Webmaster / E-Publisher Sean Ilan Materials: 6 Dec. 1999
Publishes: 10 Dec. 1999
The International Journal of Generic Drugs is the
Official Journal of the International Association of
Vol. 03 - No 08
Generic and Innovative Drug Manufacturers. Ad Closing: 10 Dec. 1999
Annual subscriptions rates for non-members US $285. Materials: 15 Dec. 1999
Institutional rate is $330 (Air mail) Reduced rates are Publishes: 31 Jan. 2000
available to accredited members of the International US & Canada - Print ISSN 0793-694X
Association of Generic and Innovative Drug
US & Canada - Electronic ISSN 0793-7415
Manufacturers - I.A.G.I.M. at $265)
The Journal is published in print and electronic editions Euro - Print ISSN 0793-7784
eight times per year in the following formats: Euro - Electronic ISSN 0793-7806
Euro - Print ISSN 0793-7784
Pacific Rim - Print ISSN 0793-7822
Euro - Electronic ISSN 0793-7806 Pacific Rim - Electronic ISSN 0793-7830

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ISSN 0793 758X US/ Canada ISSN 0793 7776 Euro ISSN 0793 7849 Pacific Rim
 I n t e r n a t i o n a l J o u r n a l o f G e n e r i c D r u g s

International
Jo u r n a l o f
In This Issue
Generic Drugs
ISSN 0793 694X - ISSN 0793 7784 - ISSN 0793 7822
CONTENTS
Electronic < Journal on Disk Vol. 03 No.08 - 2000
Journal on : the Web [email protected]
e-- Journal [email protected]
ISSN 0793 7415
Editorial Advisory & Review Board Publisher: PO Box 16075 Arlington VA 22215 USA
v
v
Dr. Colin Block MBBCh. Ph.D. Issue - Highlights
Hadassah Medical School - Jerusalem
v
Lawrence Block Ph.D.
Duquesne University, Pittsburgh - PA USA
v
ØDrug Impurities
Lional Bomzon BV Sc. Ph.D. F.R.C.V.S.
Israel Institute of Technology - Haifa Impurities in Drug Substances in 365
v
Dushen J. Chetty MSc
ANDAs.
University of Durban-Westville
CDDR Center - Rutgers University
v
Do's and Don'ts & Glossary 374
Natalie Eddington Ph.D.
University of Maryland - USA Decision trees for Impurities 376
v

ØCR Development
Clifton Canfield (Kip) Ph.D.
University of Maryland - USA
v
Hans Junginger Ph.D.
Leiden University - Netherlands
v Swelling Matrixes
Thomas S. Foster Ph.D.
Center Pharmaceutical Science & Technology Swelling Matrix Dosage Forms - 378
University of Kentucky - USA
v Choice of release Controlling
John Haigh Ph.D. Excipients
Rhodes University - Grahamstown
v
Hideki Ichikawa Ph.D.
Developing CR Formula - A 392
Kobe Gakuin University - Japan
v
CR Overview
Ronald C Li Ph.D.
Chinese University of Hong Kong From pre-formulation to the End 403
Shatin - Hong Kong Product Formulation & Process
v
Ann Neuer MBA
Medical deScriptions - Cincinnati CR Formula SOP Checklist 416
v
Ngoc-Anh T. Nguyen Ph.D. IVIVC - Metoprolol ER Tablets 416
Glaxo Wellcome Research - NC USA
v University of Maryland & IAGIM
Thornstein Loftsson Ph.D. Drug Development Association's
University of Iceland - Reykjavik
v
Joint Venture program for the Year
Jay Trivedi MS - G D Searle - USA 2000
v
Tsuyoshi Yokoi Ph.D. Year 2000 Journal Calendar 417
Kanazawa University - Japan Volume No: 03 No.08 - 2000
vv
Publisher: PO Box 16075 Arlington VA 22215 USA REPRINT ISSUE vv REPRINT ISSUE
US Fax +(1)-435-808-1891 Printer: Locum Press St. Johns Wood London UK.
vv UK Fax: +(44)-207-900-2096
vv

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ISSN 0793 694X US/Canada ISSN 0793 7784 Euro ISSN 0793 7822 Pacific Rim
 International Journal of Generic Drugs

GUIDANCE FOR INDUSTRY

Impurities in Drug Substances

Draft Guidelines
Revisited
First Issued June 1998
NO FINAL GUIDE YET
…in ANDAs
INTRODUCTION
l Qualifying impurities in the drug
D raft active drug substance guidance
published back in June 1998
provide, draft recommendations for
substance used for the ANDA that are
not found in the related USP
including information in abbreviated new monograph, scientific literature, or
drug applications (ANDAs) and innovator material;
supporting drug master files (DMFs) on l Threshold levels, below which
the identification and qualification of qualification is not needed.
impurities in drug substances The June 1998 FDA draft guidance is
produced by chemical syntheses for not applicable to the following classes:-
both monograph and non-monograph
Ø biological and biotechnological
drug substances. Impurities in drug
substances are addressed from two Ø peptides,
perspectives: Ø oligonucleotides
• CHEMISTRY ASPECTS Ø radio-pharmaceuticals
including classification and identification
of impurities, generating analytical Ø fermentation & derived semi-synthetic
reports, setting specifications, and a products
brief discussion of analytical procedures Ø herbal products
• SAFETY ASPECTS Ø crude products of animal/plant origin.
including comparative studies and
genotoxocity testing. The recommendations in this guidance
are effective upon publication of the final
Evaluate & Compare guidance (sometime in 2000) and
should be followed in preparing new
Innovator Drug applications and supplements for
changes in drug substance synthesis or
Impurities process.
Specific guidance is provided for: However, if the information in a drug
l Qualifying impurities found in the drug substance DMF cited in such an ANDA
substance used for the ANDA via a or ANDA supplement has been
comparison with impurities found in the reviewed prior to the publication of the
related USP monograph, scientific final guidance, this guidance does not
literature, or innovator material apply.
l Qualifying impurities found at higher This guidance is intended to be a
levels in the drug substance used for
companion document to the
the ANDA than found in the related USP
International Conference on Q3A
monograph, scientific literature, or
Harmonization (ICH) guidance.
innovator material;

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ISSN 0793 694X US/Canada ISSN 0793 7784 Euro ISSN 0793 7822 Pacific Rim
 International Journal of Generic Drugs

10 'RULES TO REMEMBER' can arise).

Rule No.1 - Evaluate the RLD Rule No.8. Always stress the
impurity profile (i.e. get a baseline). active in-house to see which
impurities do occur.
Rule No.2. Treat with CAUTION
or REJECT a vendor profile Rule No.9. In drug development,
HIGHER than the innovator if the active has an unknown
material. >0.1% - and it can not be reduced
- Look for an alternative supply
Rule No.3. LOOK at impurity with a better profile.
profiles in the major
pharmacopoeia (USP / BP / JP) Rule No.10. REMEMBER an
and compare with vendor's unknown impurity close to 0.1%
dedicated synthesis (comparing may grow to >0.1% on stability
profiles is important) (ageing). There's no such concept
as a safe unknown >0.1%
Rule No.4. 'Approved vendors'
may have unique impurities due to Q3A Impurities in New Drug
the purifying process. Substances.
LOOK for these 'specified [The ICH Q3A 27 guidance was published in the
impurities' in the actives Federal Register on January 4, 1996 (61 FR 371),
and issued as a Center for Drug Evaluation and
chromatograms (i.e. "Stress the Research (CDER) guidance.]
Active material").
Evaluate this
Rule No.5. Unknown impurities draft guidance
must not exceed 0.1% (if they do,
go back to active vendor to clean
side-by-side
up material). with Q3A
ICH Q3A provides recommendations for
Rule No.6. Organic impurities are
(1) inclusion of information regarding
the main focus in impuritiy profiles specified impurities in certain new drug
(Note: residual solvents have there applications (NDAs) (identified and
own guideline and limits). unidentified impurities in new drug
substance specifications) and,
Rule No.7. Do get the DMF
(2) qualification of impurities (the
holder to state the 'specific process of acquiring and evaluating
impurities' and the potential data that establishes the biological
impurities (i.e. those impurities safety of individual impurities or a given
which do arise and those which impurity profile at the level(s) specified).

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 International Journal of Generic Drugs

Generic drugs are not covered by ICH They may be identified or unidentified,
Q3A. However, many of the volatile or non-volatile, and include:
recommendations in ICH Q3A are l Starting materials
applicable to drug substances used in l By-products
generic drug products. To provide, l Intermediates
comparable processes for new and
l Degradation products
generic drug review, this guidance was
developed using the ICH Q3A l Reagents, ligands, and catalysts
framework. n Inorganic impurities may derive
At a meeting held June 22, 1993, an from the manufacturing process. They
FDA Ad Hoc Advisory Committee are normally known and identified and
recommended that there should be a 0.1 include:
percent threshold above which isolation Reagents, ligands, and catalysts
and characterization of individual
impurities should apply to chemically Heavy metals
synthesized drug substances including Inorganic salts
drug substances used in generic drug Other materials (filter aids, charcoal)
products.
n Residual solvents are organic or
For compendial materials, the USP 23 inorganic liquids (water) used during the
in General Notices and Requirements manufacturing process. Since these are
(p. 7) states that it is manifestly generally of known toxicity, the selection
impossible to include in each of appropriate controls is easily
monograph a test for every impurity that accomplished.
may arise from a change in the source
of material or a change in processing. Excluded from this document are:
Consequently, few USP monographs
Extraneous contaminants, which
have acceptance criteria for individually
should not occur in drug substances
identified impurities.
and are more appropriately addressed
However, USP has adopted a 0.1 as good manufacturing practice issues;
percent threshold for impurity
Polymorphic forms, solid state
identification via the publication of:-
property of the drug substance; and
Other Impurities in General Notices and
Requirements Enantiomeric impurities.
(Sixth Supplement, p.3636), which became official on
November 15, 1996. RATIONALE FOR THE
REPORTING AND CONTROL OF
CLASSIFICATION OF IMPURITIES
Impurities may be classified into the IMPURITIES
following categories: A. ORGANIC IMPURITIES
Ü Organic Impurities
The DMF holder or the applicant should
summarise those actual and potential
(Process and Drug Related)
impurities most likely to arise during the
synthesis, purification, and storage of
Ü Inorganic Impurities
the drug substance.
Ü Residual Solvents This summary should be based on
sound scientific appraisal of the
n Organic impurities may arise chemical reactions involved in the
during the manufacturing process and / synthesis, impurities associated with
or storage of the drug substance. raw materials that could contribute to

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 International Journal of Generic Drugs

the impurity profile of the drug commercial process should be

substance, and possible degradation identified.
products. Degradation products observed in
This discussion may include only those stability studies at recommended
impurities that may reasonably be storage conditions should be similarly
expected based on knowledge of the identified.
chemical reactions and conditions Impurity Profile Summary
involved.
When identification of an impurity is not
In addition, the DMF holder or the feasible, a summary of the laboratory
ANDA applicant should summarize the studies demonstrating the unsuccessful
laboratory studies conducted to detect effort should be included in the DMF or
impurities in the drug substance. application. Where attempts have been
made to identify impurities below the 0.1
Obtain percent level, it is useful to also report
Drug Substance the results of these studies.

Impurities Report Summaries of

from DMF Holders Un-identifiable
This summary should include Drug Substance
(a) test results of materials
manufactured during the development
Impurities are
process and batches from the proposed required from
commercial process, as well as,
(b) results of intentional degradation DMF Holders
studies used to identify potential
impurities that arise during storage. Identificationof impurities below
Assessment of the proposed apparent levels of 0.1 percent is
commercial process may be deferred generally not considered necessary.
until the first batch is produced for However, identification should be
marketing. attempted for those potential impurities
The impurity profile of the drug that are expected to be unusually
substance lots intended for marketing potent, producing toxic or
should be compared with those used in pharmacologic effects at a level lower
development and any differences than 0.1 percent.
discussed. In all cases, impurities should be
The studies (e.g., NMR, IR, and MS) qualified as described later in this
conducted to characterize the structure guidance.
of actual impurities present in the drug
substance at or above an apparent level
Do not round
of 0.1 percent (e.g., calculated using the impurity assays
response factor of the drug substance)
should be described. up to 0.1%
Note that all recurring impurities at or Although it is common practice to round
above an apparent level of 0.1 percent analytical results of between 0.05 and
(see analytical procedures) in batches 0.09 percent to the nearest number (i.e.,
manufactured by the proposed 0.1 percent), for the purpose of this

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 International Journal of Generic Drugs

guidance, such values should not be Organic impurity levels can be

rounded to 0.1 percent in determining measured by a variety of techniques,
whether to identify the impurities. including those that compare an
B. INORGANIC IMPURITIES analytical response for an impurity to
Inorganic impurities are normally that of an appropriate reference
detected and quantitated using standard or to the response of the drug
pharmacopoeial or other appropriate substance itself.
procedures. Carry-over of catalysts to Reference standards used in the
the drug substance should be evaluated analytical procedures for control of
during development. The need for impurities should be evaluated and
inclusion or exclusion of inorganic characterized according to their
impurities in the drug substance intended uses.
specifications should be discussed. It is considered acceptable to use the
Acceptance criteria should be based on drug substance to estimate the levels of
pharmacopoeial standards or known impurities when the response factors of
safety data. the drug substance and impurities are
C. RESIDUAL SOLVENTS close. In cases where the response
The control of residues of solvents used factors are not close, this practice may
in the manufacturing process for the still be acceptable, provided a correction
drug substance should be discussed. factor is applied or the impurities are, in
Any solvents that may appear in the fact, being overestimated. Analytical
drug substance should be quantified procedures used to estimate identified
using analytical procedures with an or unidentified impurities are often
appropriate level of sensitivity. based on analytical assumptions (e.g.,
Pharmacopoeial or other appropriate equivalent detector response). These
procedures should be used. assumptions should be discussed in the
Acceptance criteria should be based on DMF submission or abbreviated
pharmacopoeial standards or known application.
safety data taking into consideration REPORTING IMPURITY CONTENT OF
dose, duration of treatment, and route of BATCHES
administration. Particular attention
Analytical results should be provided for
should be given to quantitation of toxic
all batches of the drug substance used
solvents used in the manufacturing
for stability testing, as well as for
process as described in the ICH
batches representative of the proposed
guidance Q3C Impurities: Residual
commercial process. The content of
Solvents.
individual impurities, both identified and
ANALYTICAL PROCEDURES unidentified, and total impurities
The DMF or abbreviated application observed in these batches of the drug
should include documented evidence substance should be reported with the
that the analytical procedures are analytical procedures indicated.
validated and suitable for the detection A tabulation (e.g., spreadsheet) of the
and quantitation of impurities. data is recommended. Impurities should
Differences in the analytical procedures be designated by code number or by an
used during development and proposed appropriate descriptor, for example,
for the commercial product should be name or retention time. Levels of
discussed in the DMF or abbreviated impurities that are present but are below
application. the validated limit of quantitation (LOQ)
need not be reported.

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 International Journal of Generic Drugs

If analytical procedures change during Those impurities selected for inclusion

development, reported results should be in the specification for the drug
linked with the procedure used and substance are referred to as specified
appropriate validation information impurities in this guidance.
should be provided. Specified impurities may be identified or
Representative chromatograms should unidentified and should be individually
be provided. listed in the drug substance
Chromatograms of such representative specification (see below). A rationale for
batches, from methods validation the inclusion or exclusion of impurities
studies showing separation and in the specification should be presented.
detectability of impurities (e.g., on
spiked samples), along with any other
This rationale should include a
discussion of the impurity profiles
impurity tests routinely performed, can
observed in batches under
serve as the representative impurity
consideration, together with a
profiles.
consideration of the impurity profile of
The applicant or DMF holder should
material manufactured by the proposed
ensure that complete impurity profiles
commercial process.
(i.e., chromatograms) of stability
batches are available if requested. Specific identified impurities should be
A tabulation should be provided included along with recurring
comparing impurity levels between unidentified impurities estimated to be at
stability and other batches. or above 0.1 percent.
For each batch of the drug For impurities known to be unusually
substance, the report should include: potent or to produce toxic or unexpected
Batch identity and size pharmacological effects, the
Date of manufacture quantitation / detection limit of the
Site of manufacture analytical methods should be
Manufacturing process commensurate with the level at which
Impurity content, individual and total the impurities need to be controlled.
Use of batches For unidentified impurities, the
Reference to analytical procedures procedure used and assumptions made
used in establishing the level of the impurity
ACCEPTANCE CRITERIA FOR should be clearly stated.
IMPURITIES Unidentified impurities included in the
The specification for a drug substance specification should be referred to by
should include acceptance criteria for some appropriate qualitative analytical
impurities. descriptive label (e.g., "unidentified A,"
Stability studies, chemical development "unidentified with relative retention of
studies, and routine batch analyses can 0.9").
be used to predict those impurities likely Finally, a general acceptance criteria of
to occur in the commercial product. not more than 0.1 percent for any
The selection of impurities to include in unspecified impurity should be included.
the drug substance specification should Acceptance criteria should be set no
be based on the impurities found in the higher than the level that can be justified
batch(es) manufactured by the (see the Impurities Decision Tree for
proposed commercial process. generic drugs, Attachment I) either by

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 International Journal of Generic Drugs

comparative studies or genotoxicity The mass balance need not add to

studies, and unless such data indicate exactly 100 percent because of the
otherwise, no lower than the level analytical error associated with each
achievable by the manufacturing analytical procedure.
process and the analytical capability.
Mass Balances
In other words, where there is no safety
concern, impurity acceptance criteria may exceed 100%
due to
should be based on data generated on
actual batches of the drug substance
allowing sufficient latitude to deal with
normal manufacturing and analytical
analytical variance
variation, and the stability The summation of impurity levels plus
characteristics of the drug substance. the assay value may be misleading, for
example, when the assay procedure is
Erratic non-specific (e.g., potentiometric
titrimetry) and the impurity level is
batch-to-batch relatively high.
impurity levels Unknown Peaks
may indicated must not exceed
incomplete validation 0.1%
of the Labelled amount
Although normal manufacturing
QUALIFICATION OF IMPURITIES
variations are expected, significant
variation in batch-to-batch impurity Qualification is the process of acquiring
levels may indicate that the and evaluating data that establishes the
manufacturing process of the drug biological safety of an individual impurity
substance is not adequately controlled or a given impurity profile at the level(s)
and validated. specified.
The DMF holder or the applicant should
In summary, the drug substance
provide a rationale for selecting impurity
acceptance criteria should include,
acceptance criteria based on safety
where applicable, acceptance criteria
considerations.
for:
The level of any impurity present in a
Ø Organic Impurities: drug substance that is in compliance
u Each specified identified impurity with a USP specification or has been
u Each specified unidentified impurity at adequately evaluated in comparative or
or above 0.1 percent in vitro genotoxicity studies or has been
u Any unspecified impurity, with a limit evaluated via an acceptable
of not more than 0.1 percent Quantitative Structure Activity
u Total impurities Relationships (QSAR) database
Ø Residual Solvents program is considered qualified for
ANDAs.
Ø Inorganic Impurities
A summation of assay value and Note: Impurities that are also significant
impurity levels generally may be used to metabolites do not need further
obtain mass balance for the test sample. qualification.

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 International Journal of Generic Drugs

Ifdata are not available to qualify the available in the scientific literature to
proposed acceptance criteria of an qualify an impurity.
impurity, studies to obtain such data The studies that should be performed to
may be needed when the usual qualify an impurity will depend on a
qualification threshold levels given number of factors, including the patient
below are exceeded: population, daily dose, and route and
Maximum Daily Dose Qualification Threshold duration of drug administration.
Such studies are normally conducted on
≤2g/day 0.1% or 1 mg per
day (lowest value) the drug substance containing the
impurities to be controlled, although
>2g/day 0.05%
studies using isolated impurities are
Higher or lower threshold levels for acceptable.
qualification of impurities may be Levels L1 through L4 are
appropriate for some individual drugs recommendations for the type of
based on scientific rationale and level of information that would be considered to
concern, including drug class effects. provide assurance that the impurity in
For example, qualification may be question is "innocuous by virtue of
having no significant, undesirable
especially important when there is
biological activity in the amounts
evidence that such impurities in certain
present" (see USP <1086> Impurities in
drugs or therapeutic classes have
Official Articles).
previously been associated with
adverse reactions in patients. In these Only in Level L5, where concern
instances, a lower qualification regarding possible toxicity is indicated,
threshold level may be appropriate. is additional testing recommended (e.g.,
by a battery of in vitro genotoxicity
Technical factors (manufacturing tests).
capability and control methodology) may Level L6 would be for those rare
be considered as part of the justification
instances where an impurity has not
for selection of alternative threshold
been qualified. In such cases, the ANDA
levels. Proposals from applicants for
would then fall outside the purview of
alternative threshold levels will be
section 505(j) of the Federal Food,
considered by the FDA on a case-by-
Drug, and Cosmetic Act (the Act).
case basis
Additional clarification regarding the
BPC Manufacturers levels in the Impurities Decision Tree for
Generic Drugs is provided.
should decrease First level (L1):
the impurity below This level evaluates whether the
impurity in question is "above
the maximum level threshold"? See the threshold table.
(This level is identical to the
The Impurities Decision Tree for
corresponding level in the ICH Decision
generic drugs (below) describes
Tree for Safety Studies.)
considerations for the qualification of
impurities when thresholds are Second Level (L2):
exceeded. In some cases, decreasing This level evaluates whether the
the level of impurity below the threshold, "structure is elucidated?" This refers to
rather than providing additional data, structural identification or
may be the simplest course of action. characterization exactly as in the ICH
Alternatively, adequate data may be Decision Tree for Safety Studies.

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 International Journal of Generic Drugs

However, in those rare cases where it is Unidentified

not possible to identify the impurity by
structure, the efforts made should be impurities present
satisfactorily documented. Once the
impurity has been structurally identified, in both innovator &
one could go to level L3.
generic are deemed
Five of the Six
acceptable
impurity levels
In certain dosage forms where
impact on ANDAs sensitivity concerns arise, the impurity
Third Level (L3a): levels should be no higher than the
innovator's level for toxic impurities.
Compliance with a USP acceptance
In generic drugs, an unidentified
criteria for a known individual impurity
impurity may still be considered
(e.g., see impurity listed in the Clidinium
qualified in cases where the impurity is
Bromide USP monograph).
observed at similar levels in the
Third Level (L3b): A comparison of the innovator's product via a comparative
impurity profile of the generic drug study.
substance with the process impurities Third Level (L3c):
profile on an average of three or more
different lots of the innovator's drug This level looks at an impurity at a
product is recommended. "higher level, or a different new
impurity."
This comparative study should be
performed using appropriate New means one that was not previously
discriminating analytical tests such as seen in the bulk drug substance. The
HPLC or Capillary Electrophoresis. level of the new impurity may be
qualified from the scientific literature if it
Evaluate 3 or more is substantiated that this impurity is an
ordinary impurity (see USP <1086>) at
innovators lots to the levels used.
The scientific literature would include
establish ANDA's recognized scientific publications.
Impurity baseline Alternatively, the new impurity may be
qualified by lowering it to below the ICH
The impurity is qualified if it is found at threshold level, or by following the next
similar levels (no more than two-fold level in the Impurities Decision Tree for
higher for most drug substances). generic drugs.
Two-fold higher criteria are justified for Fourth Level (L4):
several reasons. For example, the Is the impurity "related to others with
innovators' impurity acceptance criteria known toxicity"? As one approach, the
are set higher than levels observed in use of a Quantitative Structure Activity
drug substances, and the safety studies Relationships (QSAR) database
that qualified the innovators' drug program may be helpful in identifying
substances are carried out at whether an impurity is related to others
significantly higher levels than the of known toxicity. The use of such a
specifications agreed to under FDA's program is acceptable to the Office of
pharmacology and toxicology Generic Drugs (OGD).
evaluations.

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 International Journal of Generic Drugs

Levels 1 to 4 If the result of genotoxicity testing raises

a concern, the need for additional
evaluate drug toxicity testing will be evaluated on a
case-by-case basis.
safety aspects Factors to be considered include the
Modules currently recommended are: therapeutic use of the drug product, its
Rodent Carcinogenicity, Developmental intended duration of use, and results of
Toxicity Potential, Ames Mutagenicity the QSAR analysis.
(five strains), and for topicals, Skin However, even in those cases where no
Sensitization. potential for concern is indicated by the
If no potential for concern is indicated genotoxicity testing, the need for further
by QSAR evaluation, the impurity is toxicity testing should be evaluated if
considered qualified, but it should not the impurity level exceeds either 1
exceed a level of 0.5 percent or 500 percent of the drug substance or 1
micrograms per day, whichever is less mg/day, whichever is lower, at the
(equivalent to 0.5 percent of 100 mg of a human therapeutic dose of the drug
drug substance), without other product.
supporting data (such as genotoxicity
test data).
If toxicity issues are confirmed by these
in vitro tests, the DMF holder or
A determination to accept the data will applicant may either purify the drug
be made on a case-by-case basis taking
substance to reduce the impurity to a
into consideration the therapeutic use of
level below the ICH threshold or go to
the drug product, its intended duration
the next level (L6) in the Impurities
of administration, and the results of the
Decision Tree for generic drugs.
QSAR analysis.
However, if the QSAR evaluation does Six Level (L6):
not provide sufficient information Animal Toxicity testing
because the program cannot perform This level involves qualification of the
the evaluation due to the lack of impurity "by general toxicity testing"
relevant information in the database, the If this pathway is used, the ANDA would
manufacturer should lower the impurity fall under section 505(b) of the Act.
level to below the ICH threshold or General toxicity testing involves animal
qualify the new impurity at the L5 level.
testing, thus an application would not be
Fifth Level (L5): deemed acceptable by OGD under
This level describes evaluation of the section 505(j) of the Act.
toxicity of an impurity via a battery of in
vitro genotoxicity tests Level Six
Wherever possible Impurity Testing
the onus is on BPC violates the ANDA
manufacturer to submission status
lower or remove The drug substance manufacturer as
the offending impurity well as the applicant should be
cognisant of this issue before the
(See the ICH Decision Tree for Safety applicant commits to extensive studies
Studies regarding genotoxicity studies). with the bulk drug substance.

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 International Journal of Generic Drugs

NEW IMPURITIES
During the course of a drug Don't exceed the RLD's impurity levels.
development program, the qualitative Don't test for other synthesis pathway
impurity profile of the drug substance impurities
may change or a new impurity may
appear, for example, as a result of
synthetic route changes, process
Glossary of Terms
optimization, or scale-up.
Acceptance Criteria:
Numerical limits, ranges, or other
The impurity suitable measures for acceptance of the
results of analytical procedures.
package depends on Chemical Development Studies:
the synthesis route Studies conducted to scale-up, optimize,
and validate the manufacturing process
New impurities may be identified or for a drug substance.
unidentified. Such changes call for Drug Substance:
consideration of the need for The designated therapeutic moiety. See
qualification of the level of the impurity also the definition in 21 CFR 314.3.
unless it is below the threshold values Enantiomers:
as noted above. Compounds with the same molecular
Unidentified formula as the drug substance, which
differ in the spatial arrangement of
below the level atoms within the molecule and are non-
Identified superimposable mirror images.
Extraneous Substance:
above the level An impurity arising from any source
When a new impurity exceeds the extraneous to the manufacturing
process.
threshold, the Impurities Decision Tree
for generic drugs should be consulted. Genotoxicity Tests:
Studies should compare the drug Genotoxicity tests can be defined as in
substances containing a representative vitro tests designed to detect compounds
level of the new impurity with previously that induce genetic damage directly or
indirectly by various mechanisms.
qualified material, although studies
(Compounds which are positive in tests
using the isolated impurity are also
that detect such kinds of genetic damage
acceptable.
have potential to be human carcinogens

Do's & Don'ts and/or mutagens, i.e., may induce cancer

and/or heritable damage.)
Herbal Products:
Do establish all the potential impurities
that can arise from the approved Medicinal products containing,
manufacturers (suppliers) synthesis exclusively, plant material and/or
pathway. vegetable
drug preparations as active ingredients.
Do collaborate with the approved
In some traditions, materials of
supplier on which residual impurities
inorganic or animal origin may also be
actually remaining in the active drug
present.
substance.
Identified Impurity:
Don't qualify an impurity if it can be
An impurity for which a structural
removed from the active material.
characterization has been achieved.

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 International Journal of Generic Drugs

Impurity: and/or local properties, as defined by

Any component of the drug substance their chemical structure and evaluated
that is not the chemical entity defined as by using an appropriate data base and
the drug substance. modules.
Impurity Profile: Reagent:
A description of the identified and A substance, other than a starting
unidentified impurities present in a drug material or solvent, that is used in the
substance. manufacture of a drug substance.
Intermediate: Safety Information:
A material produced during steps of the The body of information that establishes
synthesis of a drug substance that must the biological safety of an individual
undergo further molecular change impurity or a given impurity profile at the
before it becomes the drug substance. level(s) specified.
Ligand: An agent with a strong affinity Solvent:
to a metal ion. An inorganic (i.e. water) or an organic
Mass Balance: liquid used as a vehicle for the
The process of adding together the preparation of solutions or suspensions
assay value and levels of degradation in the synthesis of a drug substance.
products to see how closely these add Specification:
up to 100 percent of the initial value, A list of tests, references to analytical
with due consideration of the margin of procedures, and appropriate
analytical precision. acceptance criteria that are numerical
New Drug Substance: limits, ranges, or other criteria for the
The designated therapeutic moiety that tests described. It establishes the set of
has not been previously registered in a criteria to which a drug substance or
region or member state (also referred to drug product should conform to be
as a new molecular entity or new considered acceptable for its intended
chemical entity). It may be a complex, use.
simple ester, or salt of a previously Conformance to Specification:
approved drug substance. Conformance to specifications means
Polymorphism: that the drug substance and/or drug
The occurrence of different crystalline product, when tested according to the
forms of the same drug substance. listed analytical procedures, will meet
the listed acceptance criteria.
Potential Impurity:
An impurity that, from theoretical Specifications are binding quality
considerations, may arise from or during standards that are agreed to between
manufacture. It may or may not actually the appropriate governmental regulatory
appear in the drug substance agency and the applicant.
Qualification: Specified Impurity:
The process of acquiring and evaluating An identified or unidentified impurity that
data that establishes the biological is selected for inclusion in the drug
safety of an individual impurity or a substance specifications and is
given impurity profile at the level(s) individually listed and limited in order to
specified. assure the safety and quality of the drug
substance.
Quantitative Structure Activity
Starting Material:
Relationship (QSAR):
A material used in the synthesis of a
Used for rationalization and prediction
drug substance that is incorporated as
of in vivo mammalian toxicity of
an element into the structure of an
chemicals on the basis of their overall

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 International Journal of Generic Drugs

intermediate and/or of the drug Whether your firm is

substance.
Starting materials normally are an
commercially available and of defined
chemical and physical properties and INNOVATIVE
structure. or a
Toxic Impurity:
Impurities having significant undesirable Generic Company
biological activity. This key conference is
Unidentified Impurity:
for you!
An impurity that is defined solely by
nd
qualitative analytical properties (e.g., WHEN 1 - 2 March 2000
chromatographic retention time). WHERE -Thistle Westminster Hotel
Validated Limit of Quantitation:
For impurities at a level of 0.1 percent, London
the validated limit of quantitation should
be less than or equal to 0.05 percent. Profiting & Competing
Impurities limited at higher levels may
have higher limits of quantitation
IN THE EUROPEAN
GENERIC INDUSTRY
n Plus Post Conference
Workshop
The definition of 3
RD
MARCH 2000
Basic Principles of Designing
an impurity for an a Successful Bioequivalence Study
Presented by
active drug
UK
substance Pharmaceutical
Conferences

includes water
SPONSOR
International Journal of Generic Drugs
The definition of BOOK NOW - Contact:
Institute for International Research
an impurity for an (: + 44-(0)-20-7915-5055
Quote CQ1492/ CQ1492W
drug product Fax: + 44-(0)-20-7915-5056
* : [email protected]
E-*
VIEW FULL PROGRAM & SPEAKERS
excludes
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water and
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 International Journal of Generic Drugs

(No Change in DRAFT GUIDANCE as of Jan 2000)

Impurities in Active Drug Substances
Impurities Decision Tree
Generic Drugs

Qualified
Impurity

Qualified
Impurity

Qualified
Impurity

For Level 6 qualification go to ICH decision tree for additional Safety Studies
[The need to go to level six (additional safety studies) immediately
disqualifies active material for ANDA use]

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 International Journal of Generic Drugs

(No Change in DRAFT GUIDANCE as of Jan 2000)

Impurities evaluation in Active Drug Substances

ICH DECISION TREE FOR SAFETY STUDIES

Qualified
Impurity

Acceptable
justification

Qualified
Impurity

Qualified
Impurity

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 International Journal of Generic Drugs

Swelling Matrix Dosage Form

- choice of releasing controlling excipients
‘…Each release controlling agent must play its role - and all
excipients must be absolutely necessary…’

CONTROLLING EXCIPIENTS n Dissolution controlled pulse-delivery

Non active ingredients used in modified n Osmotic Controlled Systems
release (MR) solid oral dose
- Core -no bag (Osmotic pump)
preparations are initially classified as to
whether the non-active is a releasing or - Core with bag (Osmotic pump)
non-releasing controlling excipient. Non-releasing controlling excipients
These excipient polymer materials are These are inactive ingredients in the final
required to meet specific physical dosage form that do not significantly
characteristics such as the ability to effect the release of the active drug
absorb gastric fluids or water. substance from the release matrix or
Release controlling excipients controlled system. Colloidal Silicon
Release controlling excipients are Dioxide NF Magnesium Stearate NF are
inactive ingredients in the final dosage typical examples.
form that function primarily to extend the Critical Process Variables:
release of the embedded active drug A specific processing step or a unit
substance. The release rate is defined process that affects the dissolution
as the amount of drug released per unit performance and drug release from…
time when measured in an invitro
dissolution testing apparatus or via an
invivo correlation or bioequivalency test. DISSOLUTION CONTROLLED
PULSE DELIVERY
The release controlling excipient matrix H2O
may be incorporated into various
modified or controlled release systems. Alternate drug layered in
The term MR (ER or CR) is used when dissolving coats
the drug acts predominantly in the upper
GIT and Delayed Release (DR) when
active release is in the intestinal region
via enteric coating of the dosage form.
Various Release mechanisms exist - DIFFUSIONAL CONTROLLED
all achieving a controlled and
SYSTEMS - MATRIX
reproducible drug delivery from:-

n Bioerodible Matrix Systems

n Diffusional Controlled Systems
- Matrix
- Reservoir Granulated drug in varied
thickness of dissolving coats

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 International Journal of Generic Drugs

DIFFUSION CONTROLLED …the controlled formulation are termed

SYSTEMS - RESERVOIR critical process variables and are as
important as the release controlling
excipients. Examples are;
(a) particle size reduction of active
material.
RESERVOIR (b) Coating concentrations
Drug core coated in
polymer membrane (c) Thickness of erodible or diffusional
that controls release rate coats and films
(zero order)
(d) Tablet hardness.
BIOERODIBLE MATRIX
SYSTEMS
Bioerodible
matrix system
DIFFUSION CONTROLLED or swelling
controlled
SYSTEMS - MATRIX with ghost T
0
matrix

100% Drug dispersed

t1 partial erosion
in polymer

t2 at maximum erosion matrix finally disappears

Decreasing
Drug Release from Erodible
Ghost Matrix
drug in ghost ER Tablets
polymer Mode of action.
Hydrophilic matrixes consist of a drug in,
and compressed with, a hydrophilic
polymer. When these systems are
placed in GI fluids or water, they start
OSMOTIC CONTROLLED swelling and the tablet thickness
SYSTEMS increases.
Soon thereafter, polymer erosion and
drug dissolution starts occurring
together. In the majority of drug/polymer
Osmotic Drug Core
(no bag) preparations, active drug is embedded
(by standard granulation techniques) into
the polymer matrix.

H2O Rigid Semi-permeable Active drug is released in the

membrane gastrointestinal tract via contributions
from different release mechanisms.
Initially surface erosion of the tablet face
occurs and water imbibes into the
Osmotic core polymer matrix.
(drug in bag)

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 International Journal of Generic Drugs

n surface wetting (rapid)

Slow direct erosions of the polymer
n surface swelling (slow process)
matrix and erosion, after transient
swelling, at the surface with the n surface erosion (ongoing)
formation of a gel layer occur. Diffusion n surface gel formation (ongoing)
release of the drug from the polymeric n gradual inner polymer swelling
matrix results, through the swelling gel n ongoing outer gel erosion
layer, with concomitant ongoing polymer
surface erosion. At the end of the drug OVERALL DRUG TRANSPORT
release, the matrix is completely Drug molecules are released at the
dissolved, suggesting that the overall surface, as well as diffusing into the
drug release time is controlled by the inner swelling polymer (a dissolution
tablet erosion. process) and then diffusing outwards
through the swelling polymer and finally
Different polymer compositions bring through the outer gel layers…
about different degrees of drug
retardation or enhancement, which may
Povidone USP -
then be fine-tuned by varying the amount (non- release controlling excipient).
of additional ingredient components such PVP K-30 is a preferred water soluble
as plasicizers (HPC) and matrix granulating agent. It may be used as an
modifiers (PEGs). Release aqueous binder for the release
characteristics are mainly governed by controlling excipients. PVP K-90 normally
the polymer / ingredient drug embedded produces harder granulates especially in
matrix. HPMC//modified-HPMC formulations
while combinations of PVP K-30 / PVP K-
Modified HPMC Formulas. 90 intra- and extra-granularly may be
Excipients are chosen either as release used to fine-adjust the dissolution rate,
controlling excipients (RCE) or non with the purpose of mimicking the
release controlling excipients (NRCE). innovator's product.
Typical control release / extended Colloidal Silicon Dioxide NF
release ingredients in swelling (non- release controlling excipient)
bioerodible matrix formulations are found used as a glidant, it promotes granulate
as follows. flow by reducing of the inter-particulate
A swelling matrix that consists of friction. It is generally used extra-
hydroxypropyl methylcellulose (HPMC) in granularly in the formula at the final dry
two distinct forms. blending stage (Y-cone stage). Usual
The unmodified excipient as a standard target amounts for solid oral dosage
compendial HPMC (of say, viscosity forms 0.5% - 3.0%. Controlled Release
value I). dosage forms use less about 0.33% -
The modified HPMC (of viscosity value 1.0%.
II) as a standard compendial HPMC Sodium Starch Glycolate NF
which has been modified through wet (non- release controlling excipient)
granulation with an appropriate film Intra- and extra-granular disintegrant
modifier and plasicizer. promotes granulate flow and enhances
These are the two release controlling granule disintegration. May be used to
excipients of the formula existing as two offset the initial hydrophobic effect of
separate parts that will eventually be alkali lubricants in immediate release
granulated together with the active dosage forms.
material. When granulated together As an extra-granular disintegrant (added
at the final Y-cone stage) it is used in the
they form a polymeric matrix. In the GIT
end process dry mix extra-granularly with
this polymer matrix undergoes:

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 International Journal of Generic Drugs

the glidant and gives rise to rapid dosage HPC or MHEC are used as the matrix
form disintegration. NMT 5.0%, target 1.0 - swelling modifiers, affecting both dissolution
4.0%. Intra-granular incorporation tends to and diffusion (generally used in smaller
disintegrate the granule too rapidly and amounts ranging from 2-10%) and may be
enhances the dissolution profile (promotes formulated in conjunction with a variety of
rapid dissolution). low M.W. plasticisers (Low molecular weight
Magnesium Stearate NF - (non- release grades of polyethylene glycols (PEG 4000) /
controlling excipient) carbowaxes; or propylene glycol or even
triacetin.)
The excipient is used us a lubricant. Carbomer 934P NF. - (Release
Lubricants are primarily used to prevent
powder from sticking to the tablet tooling controlling excipients.)
and to reduce the friction between the die Modifies bioerodible HPMC matrix
wall and the tablet as it is being ejected. component - both as a matrix component
Usual target amounts for solid oral dosage modifier and a plasticiser for swelling
forms including controlled release forms is (diffusion and dissolution) controlled
around 0.5% - 1.0%. A minimum of dry release matrix systems. The carbowaxes
blending is required (in the final stage normally do not exceed 1% - 10% in CR
blending.)
HPMC/ modifiedHPMC formulations.
Hydroxypropyl Methylcellulose USP,
Target levels chosen 0.75% -1.0% of the
Hydroxypropyl Cellulose NF
overall formula and 2-4% of the modified
HPMC//modified-HPMC formulations
comprise of wet granulating HPMC with a
cellulose derivative.
modified pre-granulated HPMC. The Coating Ingredients - Standard Opadry™
formula are used, obtainable from
unmodified and modified HPMC
Colorcon®. Contains Hydroxypropyl
components forms the basis of the release
Methylcellulose NF as major components of
controlling excipients in bioerodible the aqueous film coat. Highly compatible
swelling matrices. Various viscosity grades with HPMC / HPC formulations.
of HPMC are available. (methocel™
K100LV;K4;E5) Excipient exposure
These well known compendial controlled For ANDA submissions, the excipient should
appear in the FDA’s Inactive Ingredient
release excipients are capable of
Guide (IIG). This guide lists inactive
producing a slowly swelling, bioerodible
ingredients that have been safely used in
matrix, in an extended release dosage currently marketed OTC and prescription
form. The release rate can be adjusted up drug products for a specific route, in this
to 16 - 20 hours. The ratio of HPMC to case for oral use.
Modified-HPMC used, normally ranges
The second condition for the non active
from 1:1, 2:1 to 3:1
ingredient is that the percentage amount
Ratios of 75 HPMC : 25 HPMC (modified) used in the product formula should not
are excellent starting points for exceed the maximum percentage for the
development and generally, the total specific route (e.g. oral use) as stated in the
HPMC content constitutes approximately Inactive Ingredient Guide.
1/3 to ½ of the overall tablet weight. The The maximum quantity of a specific non
actual amount depends on of quantity of active ingredient is generally determined by
active material in the CR dosage form. the FDA as the highest amount of non active
In HPMC//modified-HPMC controlled that is currently approved for an OTC or
formulae the most practical approach is to ANDA product for that specific dosage form
choose the appropriate ratios and viscosity or route of administration.
grades of the HPMC for the modified and ANDA approvals may be OTCs or
unmodified portion via repeated dissolution prescription products. The above FDA
testing of small development batches internal rule apply only to ANDA
Normally two different grades of HPMC submissions and do not apply to OTC non-
USP/NF are granulated together. ANDA products.

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 International Journal of Generic Drugs

Choosing non-active excipients ERODIBLE ER TABLETS

Excipient-to-excipient interactions (color (General scheme)
effects and incompatibilities) must be
excluded. Uniformity of Content for
granule and tablet may be impacted by HPMC
the physical specifications of the wet granulated
excipients. with
Generic manufacturers who evaluate the Plasicizer
Modifier
reference listed drug (RLD) and design a
Q&Q formula may minimize fluctuations
in dissolution and bioequivalent testing.
General Excipient Rules:
The non-active should ideally be HPMC Modified
compendial (USP/NF; BP; EP; JP etc.) Grade HPMC

• The non-active should ideally be in the

Handbook of Pharmaceutical Excipients Define
(current 2nd Edition) Aqueous Wet Granulation Blade Speed &
or times
• The non-active should be in the FDA’s alcoholic
IIG-Inactive Ingredient Guide regarding
⇒ same dosage route only
⇒ maximum percentage not exceeded.
• If the non-active is for an OTC tablet Control
screen size
product only (not an ANDA) then it should
FBD Drying (~0.8mm)
be at least in the GRAS. lists.
Milling
• It is strongly recommended that non-
actives selected for ANDA formula are
subject to approved supplier procedures
that is similar to Active Ingredients.
Inactive ingredients specifications Excessive
Inactive ingredients with unspecified lubricant
blending time
physical size parameters may require causes large
quality control in two critical physical dissolution
specifications (e.g. Magnesium stearate) RSD variations
◊ particle size specification
Control
◊ bulk density specification lubricant
Uniformity of Content-Granulate studies Dry Blending Blending Time
It is important that generic manufacturers Lubricant (Max. 5 min)
Disintegrant
correlate excipient specifications and
evaluate the impact on the bulk granulate
‘uniformity of content’ assay during in-
process manufacture. Lubricated and un- Tabletting
&
lubricated granulation studies evaluating Film Coating
Content Uniformity and dissolution are
recommended. Specifications for particle Tablet Weight
size and bulk density ranges should be in-process &
clearly specified in order to prevent Film Weight
significant differences (< 5%) in batch-to- Controls
batch and intra-batch dissolution assay RSD = Relative Standard Deviation
values.
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 International Journal of Generic Drugs

Formula polymers are modified where drug Dissolution curves for Verapamil SR produce
SOLUBILITY changes i.e.: a sustained release of 8 hours with the
n Freely soluble actives following dissolution profile
n slightly soluble actives.

240 mg Dissolution Tolerances

VERAPAMIL 240 mg SR Tablets Hours Amount Dissolved %
(using modified hydroxypropyl cellulose1)
1 (HCl) 8-20
2 (SGF) 15-35

HPC 3.5 (SGF) 35-65

wet granulated with
Plasicizer (3% lecithin)
5 (SGF) 55-85
Modifier added for 8 (SGF) >80
fine tuning
Pharmacopeial Forum Vol. 21, No 6

HPMC Modified
(39%) HPC (10%) CARBIDOPA LEVODOPA
50/200mg Extended Release
Tablets
(Formulated with HPC/Carbowax modified
Wet Granulation hydroxypropylmethyl cellulose1)

Carbidopa
(18%)
To Granulator Modified HPMC
Add HPC ~ 2-4%
FBD Drying Levodopa
Modified HPMC Carbowax ~1%
Milling (66%)
(8%) HPMC [1] ~ 60%
Color
HPMC [2] ~ 36%
(trituration)

99.9% Alcoholic
Dry Blending Wet Granulation High Shear
Lubricant Granulator
(12%)
Disintegrant control blending
times and
speeds
FBD Drying
+ Milling
(0.8 mm)

Tabletting
& Stearate Non-Alkali
Dry Blending
Film Coating blending Stearate
Lubricant
time Glidant (0.5%) (2-4%)
(5min)

1
With acknowledgments:- Handbook of Generic Development
Controlled Release Tablets Volume 10 Edition 03 - Locum Tablet Weight
International Publishers Series ©2000. in-process & Tabletting
Film Weight &
Controls Film Coating

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 International Journal of Generic Drugs

LOW LOADING DOSE - NON-AQUEOUS HIGH LOADING DOSE - Water Soluble

FELODIPINE 2.5 mg ER Tablets (using alcoholic Erodible ER Tablets - (General Scheme)
hydroxypropylcellulose (HPC))
HPMC
ALCOHOLIC (1) wet granulated
Felodipine with
Antioxidant Plasicizer
ALCOHOLIC (6) Modifier
HPC (5%)

HPMC Modified
HPMC (High MW 10%) HPMC
HPMC (Low MW 30% )
[Alcoholic granulation] 2nd Alcoholic
40% Filler (Lactose) Granulation
Intra-granular disintegrant
Wet Granulation
of Aqueous PVP
HPMC & Granulation
Modified HPMC

FBD Drying
Milling
IPQC
FBD Drying LOD
Milling Screen Size
Dry Blending
Non-alkali
Lubricant
Dry Blending -Y-Cone
Add Alkali Lubricant +
Extra granular Disintegrant
Tabletting
&
Coating

Tabletting
&
Dissolution curves produce a sustained Coating
release of 10 hours with the following
dissolution profile

Felodipine 2.5 mg Dissolution Tolerances

Hours Amount Dissolved % Establish Possible
1 1-10 IVIVC
2 10-30
6 42-68
10 NLT 75 (Individual)
10 NLT 80 (mean)
USP App. No 2, 50 rpm
Paddle below stationary basket, Bioequivalent
Buffer pH6.8 1%SLS STUDY

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 International Journal of Generic Drugs

Table 4.1
Common Controlled, Modified, Delayed and Extended Release coating materials

Generic Name Abb. Soluble in Properties

NON ENTERIC COATS

Ethylcellulose EC Ethanol, IPA Low Viscosity Aqueous films
(DOW) organic solvents
Hydroxyethylcellulose HEC GI Fluids, Water Low Viscosity Aqueous films
(Union Carbide) giving clear solutions
Methylcellulose MC GI Fluids, Water, GI Fluids, Water insoluble
(Methocel™) (DOW) organic solvents Used as a film tougher
Methylhydroxyethylcellulose MHEC GI Fluids GI soluble film former
(DOW)
Hydroxypropylcellulose NF HPC GI Fluids, Water, Component in swelling or
(Klucel LF™) (Hercules) ethanol eroding polymers/matrixes
Hydroxypropylmethyl- HPMC GI Fluids, Water, Component in swelling or
cellulose NF (DOW) ethanol, eroding polymers/matrixes
(Methocel HG/ K-15 /E-5™) Methylene Cl
Sodium carboxymethyl- Na CMS GI Fluids, Water, Adjuvants as film formers /
cellulose (Hercules) ethanol film modifiers
Polyethylene Glycols PEG GI Fluids, Water, Used as film modifiers / coat
organic solvents plasticisers
Carbopol 934 P Carbo- GI Fluids, Water, Adjuvants as film modifiers /
(Union Carbide) waxes organic solvents coat plasticisers

ENTERIC COATS
Cellulose acetate CAP IPA, Acetone, ethyl Dissolves in distal end of
(Kodac) acetate, alkalies duodenum - add plasticisers
Hydroxypropylmethyl- HPMCP IPA, Acetone, Dissolves in proximal end of
cellulose phthalate (Shinetsu) alkalies pH > 4.5 duodenum
Methacrylic acid co-polymer Eugragit Solubilized in alkali media
-L pH > 6 Combinations used as
-S pH > 7 Enteric coating plus
sustained release
Polyvinyl acetate phthalate PVAP IPA, Acetone, Dissolves in full length
(Colorcon) alkalies pH > 5 duodenum
Methacrylic acid esters Combinations used as
Enteric coating plus
sustained release
Methacrylic acid polymers Combinations used as
Enteric coating plus
sustained release
Shellac BPC 1963 MAP GI Fluids, Water Batch variability - irregular
pH 7 release - non reproducible.

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ØC H E C K L I S T ×
CL # P-HPGD-03-Y2K

Non active ingredients

‘qualify the excipient performance at both ends of the given
specification range’
‘qualify the process performance with the chosen excipients’

1. Has the RLD’s non actives been qualitatively identified ? nYes nNo
2. Are releasing and non-releasing controlling excipients identified? nYes nNo
3. Are the non actives referenced in the FDA’s IIG book? nYes nNo
4. Has the maximum percentage not been exceeded for oral tablets? nYes nNo
5. Has the particle size and bulk density of key non actives (e.g. nYes nNo
lubricants) been specified with an appropriate range?
6. Is the dissolution profile of the proposed generic formula similar to nYes nNo
the RLD's profile?
7. Are the comparative 12 point dissolution values all within 5% of the nYes nNo
RLD dissolution profile under normal and accelerated testing?
8. Is the granulation uniformity of content spread less than 4.0 - 5.0% nYes nNo
with RSD , <6.0%?
9. Does the development protocol indicate that the final formula is nYes nNo
manufactures at the lower and upper tabletting speeds ?
10. Does the firm regularly review the Pharmacopoeial Forum for nYes nNo
proposed monographs and specifications for non-compendial
excipients?
11. Has the firm reviewed all the suppliers for potential ‘Approved nYes nNo
Suppliers’ as listed the Handbook of Pharmaceutical Excipients?
12. Is Purified Water USP used as an approved excipient granulating nYes nNo
agent and coating suspension ingredient?
13. Have all the excipient specifications been reviewed in USP / NF, nYes nNo
Ph. Eur / BP, and JP and the latest supplements and addenda?
14. For compendial excipients has the latest supplement been nYes nNo
checked?
15. Does your generic firm have a current ‘ Approved Supplier SOP ' nYes nNo
for non active ingredients?
Footnote : The words non active ingredient; inactive ingredient and excipient are all the same meaning and interchangeable in use.

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 International Journal of Generic Drugs

Non Release Controlling

Excipients
‘…Challenge the adjuvant systems during development
and then optimize their formula concentration…’

Non Releasing Ingredients the drug product's impurities during

product aging.
N on release controlling ingredients
are, antioxidants and chelating
systems as well as lubricants and
The anti-oxidant system may well
degrade significantly with time and
disintegrating excipients. They are not therefore does not require any
active ingredients nor are they neutral qualification or testing of its upper and
inactive ingredients, such as simple lower operational limits.
inert fillers but beneficial and essential
non release controlling excipients, as Solubility additives
they maintain the product quality and
physical characteristics, as well as may enhance both
inhibiting impurity / degradant growth
and enhancing processing ease and
active & antioxidant
shelf life stability of the final product The addition of a solubility enhancing
formula. agent may enhance the dissolution
CHOOSING NON ACTIVE parameters of a poorly soluble active
INGREDIENTS. ingredient and in parallel improve the
The evaluation of non release anti-oxidant performance.
controlling excipients requires a Typical solubility enhancers (Tween 80 or
Polyoxyl 40 Hydrogenerated Caster Oil -
thorough optimization and qualification
Cremophore RH40™) may at times have a
protocol for:
greater impact on the active drug
n the anti-oxidant / chelating agent dissolution profile and a probable
combination systems reduction in tablet hardness, than
n Solubility enhancing agent(s) enhancing the antioxidant activity of
poorly soluble antioxidant agents.
n Agents
n Lubricant(s) It is important to establish and validate
the impact of the antioxidant on drug
Most non actives assay and impurity profiles during the
formula development (optimization)
ingredients are stage. Following this development path
the actual antioxidant loss need not be
Non-controlling routinely assayed during the product
Release Excipients development stage
commercial production.
or during
Anti-oxidant and chelating agent
combination systems Optimize the
These systems maintain an active role
by (a) minimizing the potency loss of the
overall antioxidant
active ingredient(s) and (b) stabilizing system

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Formula Optimization: development can result in reduced QC

An anti-oxidant optimization protocol will routine finished product testing.
enable drug developers to fully The first three commercial validation
eliminate antioxidant release and check lots do not require antioxidant release /
specifications from routine product stability check testing as their formula
release and stability testing inclusion was qualified during the
requirements of the (pivotal) and development optimization phase.
subsequent commercial marketed Product release specifications must not
batches of the specification type: become, in part, a substitute for
incomplete development validation
Release specification: 85.0 -105.0%. testing.
Check specification: 55.0 -105.0% All pharmaceutical development
Tablet formulations can and do
units conducting drug research and
development in to controlled release
consume the antioxidant system during
the product’s shelf life. Heavy metals dosage forms should have a
may act as catalysts and degrade active comprehensive set of development
and semi-actives. Thus the need to SOPs specific to MR formulations.
evaluate the chelating agent in The primary purpose of the SOP is to
combination with the antioxidant arises. translate the various regulations and
Evaluating the total summed heavy guidelines, which are open to
metal content of the combined interpretation, into clear and concise
excipients (from their Certificate of sets of working instructions.
Analyses) may provide a starting The following key development
baseline for the choice of a suitable Standard Operating Procedures (SOPs)
combined antioxidant/chelating agent. among others are recommended for a
Antioxidant release and check controlled release development unit.
specifications ranges, as above have a
IJGD-00-069Y - Choosing Non
very limited value in a drug
Actives Ingredients for Modified
development program. It may be
Release formula development.
appropriate to evaluate once the total
quantity of antioxidant consumed during IJGD-00-069Y Vendor Certification
a three/six month accelerated stability Requirements for Approved Non
evaluation. Release Controlling Excipients
The development formula optimization
should tabulate the loss of assay IJGD-00-069Y Checking Excipient in
potency and impurity / degradant growth the FDA ‘Inactive Ingredient Guide.’
for the active substance over an IJGD-00-069Y Evaluation and
accelerated shelf life period of 0,1, 2, 3 classification of Release Controlling
(and 6) months at 400C / 75% RH Excipients in MR / ER formulations.
This formula optimization procedure
simply eliminates any routine IJGD-00-069Y Dissolution testing
antioxidant testing in the future. and evaluation of extended release
solid oral dosage forms
These antioxidant qualification studies
are needed during the product IJGD-00-069Y Development, use
development stage and once and evaluation of Invitro Invivo
performed, close the requirement for Correlations in extended release solid
any further testing. This is an important oral dosage forms
example of how careful product

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 International Journal of Generic Drugs

Release Controlling Excipients

CHOOSING AN ANTIOXIDANT /
SOLUBILITY ENHANCING / An excipient in the final dosage form
CHELATING SYSTEM whose primary function is to modify the
duration of the release of the active
drug substance form the dosage form.
Choice & Selection of Defined as a Critical Composition
Development formula
Variable.
Developers should provide appropriate
justification (i.e. with supporting data of
Trial Formula containing the mechanism of drug release and
antioxidant systems manufacturing process) for claiming any
Re-formulate
(Combinations & Excipient as a Release Controlling
Strengths) Excipient in the formulation of the
modified release solid oral dosage
form).
CHECK & EVALUATE The functionality of the Release
Tablet Hardness
and dissolution Controlling Excipient should be
identified and stated as to the reason
for its inclusion into the formula.
If OK IF NOT
Non-Release Controlling Excipient:
An excipient in the final dosage form
CHECK & EVALUATE whose primary function does not include
Tablet modifying the duration of the release of
ASSAY &
IMPURITY PROFILE
the active drug substance form the
dosage form. These non release
controlling excipients (NRCE) are
defined as a Non-Critical Composition
Select Best Fitting Variables.
Formula for
OPTIMIZATION Note: the primary function of the
& excipient does not significantly affect the
QUALIFICATION release of the active drug substance.
(e.g. Magnesium stearate affects
dissolution but not significantly.)
Developers should provide appropriate
Formula justification for claiming any Excipient
& as a Non-Release Controlling
PROCESS Excipient in the formulation of the
OPTIMIZATION modified release solid oral dosage
form).
Consideration should be given as to
whether the excipient is critical or non
critical to the drug release.
PROCESS
QUALIFICATION The functionality of each Non-Release
Controlling Excipient should be
identified and stated.

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 International Journal of Generic Drugs

Ø CHECKLIST×
CL # HPGD-03-Y2K

Validating the Semi Active Ingredients

‘ don’t test a semi-active after it has been qualified...’

1. A full development validation/qualification study of the antioxidant has nYes nNo

been performed during the development process?

2. Has a range of antioxidant percentages been qualified by development nYes nNo

optimization studies. (e.g. lower [0.05%] middle [0.10%] and upper [0.15%])?

3. Does the antioxidant percentage selected represent the lowest % value to nYes nNo
minimize impurities and degradants during the inferred product shelf life?

4. Has the overall excipient formula been evaluated for total heavy metal nYes nNo
content from the inactive C of A's and product specification data sheets?

5. Have reducing agents, antioxidant synergist and sequestering agents that nYes nNo
have not been appropriately validated, been excluded from the product
formula?

6. Does the active ingredient remain in the check specification range (90.0 - nYes nNo
110.0 of labeled amount) at the end of accelerated stability testing?

7. Does the potency of the active ingredient decrease when the chelating nYes nNo
agent is removed from the product formulation during normal and aging
studies?

8. Have range studies been performed to evaluate the optimum amount? nYes nNo
9. Has the product formula been evaluated at lower, middle and upper nYes nNo
antioxidant percentages and evaluated against active assay values?

10. Has it been clearly established that the inclusion of chelating or an nYes nNo
antioxidant synergist positively enhances the action of the antioxidant?

11. Has potency loss of the semi actives been fully demonstrated during the nYes nNo
product development stages to establish valid specification ranges?

12. Does the stability testing protocol only evaluate formula specifications nYes nNo
that are directly impacted by the aging process ?

13. Has a complete product development profile of the antioxidant been nYes nNo
evaluated in order to eliminate routine release and stability testing of the
antioxidant agent during commercial manufacture ?

14. Is the stability testing protocol for the pivotal batch a logical nYes nNo
development sequence from the product development work ?
Footnote :
Bold numbers in checklist indicate this work must be qualified and or validated before
manufacturing the Process Qualification Batch, which actually marks the end of the product
development stage.

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 International Journal of Generic Drugs

Essential
Pharmaceutical
Generic D r u g
Series ISSN 0793 7407
Development
A Series Publication in association with

e-SOPs ™
The International Association of Generic
& Innovative Drug Manufacturers.

nPharmaceutical
n Analytical Electronic Standard Operating Procedures.
Available on 3.5” 2MB electronic disks
for immediate in-house use. Guidelines
n Decision Trees provided on how to convert
development SOPs into your own
n Bioequivalency customized research-based-
development system that meet all
n Microbiological international regulatory guides,
guidelines and regulatory requirements.
e-SOPs™
e-SOPs can be edited to meet your
n Quality Control development units own in-house needs.
Designed for Generic and NDA use.
n Scale Up
CD ROM development and process
n Cleaning Protocols
SOPs provide complete Development,
Formulation, Scale-up, Process
Qualification; pivotal and final validation
n All Validations batches; analytical, cleaning and
process validation; essential
n Regulatory documentation and OGD regulatory
know-how that is essential for a
n Pre Approvals-PAIs successful product development and a
speedy FDA approval, saving queue-
time and development dollars.
n Annual Reports
Essential information for Development
Pharmacists, R&D Chemists, QA and
e-SOPs Regulatory personnel. Allows
management to understand the nuts
and bolts on Generic ANDA and EC
DEVELOPMENT and filing in the most
cost effective way.
CD ROM available at: $299.
In association with the
International Association of Generic Drug Manufacturers. -
Locum International Contact info@ l o c u m . c o . i l
Locum Publishing House Fax: + 972-9 7494 532 / 965
A Locum House Publication
©Copyright LOCUM 1994 -2000

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 International Journal of Generic Drugs

CONTROLLED RELEASE OVERVIEW

Developing CR Formula
‘…plan the development stages into a CR Development SOP
- then carefully work the strategy of what you planned to do‘…

CR DEVELOPMENT does not necessary imply instant

bioequivalence. Adjustment are
Developing controlled release (CR) usually made to the pilot study
dosage forms differ in two significant formulation or dissolution parameters
aspects when comparing to the in order to establish an initial Level C
development of immediate release (IR) IVIVC using a single point correlation
formulations. Firstly they consists of around the Cmax. (obtained from the
two distinct types of ingredients other
than the active. These ingredients are: single dose cross-over biostudy
plasma levels.)
n Release Controlling Excipients
n Non-release Controlling Excipients Rule Two
Match the
Both types of controlling excipients
need to be well chosen, optimized
through a series of trial formulations Dissolution Profiles
and finally qualified - both qualitatively
and quantitatively. in Multimedia
Rule One A Level C IVIV correlation obtained
from a pilot biostudy can be useful in
Qualify the the 'pilot formulation development' of
the controlled release preparation. CR
Controlling Excipients developers usually produce three very
similar formulated preparations (with
Release and Non-release 'slow', 'medium' and 'fast' dissolution
The second key development stage is profiles, ~10 - 15% apart) and then
to achieve matching dissolution evaluate an appropriate correlation.
profiles between the developing Keeping the number of pilot biostudies
formula and the reference drug and to a minimum is an essential cost
then establish an in-vitro in-vivo effective tool. One pilot study (3-6
correlation of the controlled release volunteers) prior to the IVIVC and full
preparation to the reference product. scale bioequivalence study is all that is
The preferred way to establish an generally needed.
IVIVC is to undertake a single dose
cross-over pilot biostudy when the
Rule Three
formula has been fully fleshed out to
the final formula development status.
Do a Single Dose
Problems with developing CR formulas PRE-IVIVC Biostudy
are that 12 point comparative
dissolution profiles (CDPs) can be Two matching processes are evolved.
formulated to match the innovator's Initially harmonizing the test and
profile or nearly superimposed upon it, reference CDP to coincide. Secondly
however this converging correlation adjusting the dissolution profile in the

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 International Journal of Generic Drugs

media of choice, and other dissolution basket & paddle (100;150 / 50;75 rpm).
media, pH and agitation parameters Generally the lower the solubility of the
designed to highlight and discriminate active material in the matrix the higher
test & reference drug differences. the rpm speed may be required.
The first is to develop an equivalent Do develop invitro dissolution
formula and the second to obtain a methods that DO discriminate between
possible Level A correlation. various formulations and process
Rule Four
procedures.
Do fix this discriminating dissolution
Establish a Level A procedure well before any single dose
pilot study or full IVIVC is undertaken.
IVIV Correlation Do optimize the discriminating
Study Subjects: dissolution procedure to get the best
Bioavailability studies for
IVIVC 1:1 correlation once the invivo
development normally contain parameters are known.
sufficient subjects (healthy volunteers) Do incorporate time scaling as long as
to adequately characterize the the time scale factor is the same for all
performance of the controlled release formulations tested.
drug product. Various scenarios exist. Don't compare different formulations
In IVIVC Studies on different time scales.
Don't use a Level B Correlation for
Subjects May regulatory purposes as these do not
Range from 6 - 36 discriminate between different
A well formulated CR preparation formulations that display similar mean
resident plasma time curves.
supported with extensive comparative
dissolution profiles can reduce the ADEQUATE DATA
number of subjects (& cost) required. An important concept in CR IVIV
A initial pilot study requiring a Level C: development is that the less data
needs 3 - 6 subjects (Initial mini-single available the poorer the predictive
dose studies with 1-3 subjects have ability. Thus more data will be needed
been used to obtain AUC, Cmax. Tmax. to predict a complete IVIV correlation.
Enhancing this data quality by
and an indication of the overall shape
evaluating different formulations (~3)
of the plasma concentration curve for
with up to 10% differences (percent
ongoing formulation development).
dissolved) in invitro dissolution profiles
Advanced studies requiring full IVIVC would produce different invivo release
subject data sets have ranged from 6 rates and thus differing plasma
to 36. New drug formulations (NDAs) concentration levels.
tend to have greater subject numbers
(up to 36) than ANDAs (as low as 6). INDEPENDENT DISSOLUTION
Do's and Don'ts. If invitro dissolution is shown to be
independent of the dissolution
Do check the active solubility at conditions (e.g. pH and agitation) and
different pH values (pH1.2 ; 4.5 ; 6.8) if the invitro dissolution profile is
Do check the drug product's shown to be equal to the invivo
dissolution profile in different pH absorption or dissolution profile, then
media (pH1.2 ; 4.5 ; 6.8) the results for a single formulation
Do check the dissolution profile at (one release rate) are generally quite
different rpm speeds using both the sufficient data.

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 International Journal of Generic Drugs

THE CR DEVELOPMENT SOP THE DEVELOPMENT REPORT

The development SOP for controlled The development report documents all
release dosage forms is a vital the results of the development process
document that contains each stage of as highlighted from pre-formulation to
the development process of the new the pivotal batch filing of the ANDA
generic drug up to and including the The development notebooks and
pivotal batch (submission batch). interim reports provide the basic data
This document brings all the & results to this development report.
interacting departments, i.e. The development report is completed
pharmaceutical, analytical (assay and after the pivotal batch has been
dissolution) and stability units together packed, tested and placed on
to form one development program. accelerated stability. All product
CREATE IVIVC specifications, procedures and
qualifications are completed prior to
checklists and starting the pivotal batch manufacture.
development criteria Major development stops at the
conclusion of this batch.
The overall development procedure
This batch is the ANDA demonstration
requires that the product formula,
batch for filing with the FDA that
manufacturing process, controls and
demonstrates a well developed,
final product specifications (including
rugged product formula and process.
stability) are formulated, optimized and
qualified through a series of lower and AN EFFECTIVE IVIVC
upper limit formula and process Eliminates Post
specification qualifications during the
overall product development phases. Approval Biostudies
These composite validation Scale-Up and Post Approval Changes
qualifications are demonstrated again (SUPAC-MR) are permissible after the
for regulatory purposes in a finalized, pivotal batch but MUST follow the
single, continuous process during the SUPAC-MR rules for each change
manufacture of the pivotal batch and made. Where an IVIVC exists
further demonstrated in the three additional biostudies for post approval
validation (commercial) batches. changes are seldom warranted
The validation process shows that all The three validation batches, - sold as
the ranges and limits in a commercial products, demonstrate that
manufactured batch, produce the the formula and process consistently
desired drug product according to the give the same product specifications
written specifications. and are comparable to the
Optimization and qualification of bioequivalent batch (i.e. pivotal).
specification limits and process para- The development process simply
meters are developed before the establishes the ruggedness or robustness
pivotal batch manufacture, in specific of the formula, manufacturing process,
development batches, namely the product specifications and the type of
process optimization (PO) and equipment used. The pivotal and
qualification batch (PQ). The PQ batch validation batches initially demonstrate
is in fact the real end point of the and then later prove the consistency of
product development phase. the overall drug product and process.

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 International Journal of Generic Drugs

ØC H E C K L I S T ×
CL # HPGD-03-Y2K

DEVELOPING CR FORMULA
‘…combine the development stages into an overall 'Development Report'
- what did you really do?…’

1. Is a ‘Development SOP’ for the CR / MR dosage form available? qYes qNo

2. Does a SOP specifying the contents of the Development Report? qYes qNo
3. Is the active ingredient characterized for particle size and bulk density (crystal qYes qNo
structure / polymorphism) for each approved supplier?
4. Are the source and supply of the excipients characterized? qYes qNo
5. Is the source and supply of the container/closure characterized (1998 Guideline) qYes qNo
6. Does the SOP indicate that non-compendial active material assays requires a qYes qNo
validation and stability indicating assay?
7. Does the SOP required full analysis of the reference listed drug (RLD), its qYes qNo
impurity profile and stability characteristics?
8. Is an historical listing and summary of all experimental batches manufactured qYes qNo
required by a SOP?
9. Is a multipoint dissolution profile of the product formula at key stages required qYes qNo
and compared to the RLD? Are IVIVC investigated (Sept.1997 Guideline1)
10. Do the critical manufacturing procedures, critical process parameters and key qYes qNo
in-process controls require optimization and verification studies ?
11. Is a process of tightening / qualifying the product specifications, (based on qYes qNo
batch analysis) evident as the development process undergoes optimization?
12. Does the development process identify the critical processing steps for the qYes qNo
validation protocol with the potential to affect the product?
13. Hardness and dissolution tests qualified (Tablet Hardness Qualification)? qYes qNo
14. Does the analytical development require a final validated assay and stability qYes qNo
indicating (SI) assay well before running the pivotal batch?
15. Are stability study assays of the PO and PQ batch required to be tested by the qYes qNo
validated assay procedure and SI analysis?
1
Development Evaluation and Application of In Vitro/In Vivo Correlations (September 1997 BP2)
Footnote : Bold numbers in checklist indicate that this work must be checked and approved before formulation work starts.

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 International Journal of Generic Drugs

CR Formula Development
‘…research and evaluate the reference listed drug thoroughly…'

ANDA Preparations aging profiles are similar.

In-active ingredients (excipients)
The development of a oral dose CR
tablet requires seven key decisions The product formula of the generic CR
points:- oral tablet does not have to contain
the same inactive ingredients at the
♦ reference listed drug (RLD)
same quantities as the RLD, as do
♦ active material (source/supply) sterile or semi-solids dosage forms.
♦ non-active ingredients (source/supply) The qualitative ingredients are
♦ container-closure system (as RLD) required to be in the OGD Inactive
Ingredient Guide (IIG).
♦ Invitro Invivo Correlation data The FDA publish the Inactive
♦ Comparative dissolution procedure Ingredient Guide. Inactive ingredients
♦ Bioequivalence to the (RLD) found in approved drug products in the
The RLD is chosen from the FDA US are listed in the IIG.
'Orange Guide' (now on the Internet). The amount of the non-release
(‘Approved Drug Products with Therapeutic controlling excipients and release
Equivalence Evaluations’ - current 18th Edition controlling excipients in the product
1998).
formula should not be greater than the
Active substance highest concentration previously found
The active drug substance is chosen in an approved product for the same
according to standard criteria. Correct route of administration (i.e. oral route)
choice is both critical and time Development SOP’s are clarifying the
consuming. Key parameters include:- choice of inactive ingredients for pre-
♦ Analytical profile - similar to RLD formulation and formulation
under normal and stress conditions. development are an effective tool.
♦ Impurity profile - similar to RLD The choice of a well known excipient
under normal and stress conditions. manufactures with an established
♦ Approved supplier must meet all excipient range is very important as
ANDA regulatory documentation long term stability, dissolution and
requirements. aging problems are minimized or
avoided. Thus source and supply of
♦ Active Material specifications inactive ingredients for oral CR tablets
remain constant - batch-to-batch are paramount.
(not R&D or non-commercial batch)
Container closure systems
♦ Able to supply for the next 8-10 The drug product container-closure
years at the similar specifications system should be a similar material
after ANDA (pivotal) batch composition as the RLD container-
manufactured. closure system.
Using the RLD’s Active Material The degree of product protection by
Ideally the same supplier of the active the container-liner-closure system
drug substance as used by the RLD, is must prevent physical, chemical and
the most cost-effective in the long microbiological changes on storage
term, as IVIVC, stability, impurity, and and during customer-consumer use.

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 International Journal of Generic Drugs

USING A TYPICAL IVIV MODEL

Development Formula Development Formula
(dissolution dependent) (dissolution independent)

prepare
SLOW
MEDIUM
FAST profiles Optimum Formula

Fine tune 12 point comparative dissolution

FORMULA profile (USP Apparatus I or II)
discrimination
via different
dissolution
Pilot study An pilot
media and
(Formula Development) 1-3 subject
settings.
(1-3-6 subjects) mini-study
may reduce
development
time
(Level C
Adjust pilot formula guide)
Release controlling excipients
Deconvolution calculations
If necessary
alter
Adjust formula dissolution
or process 12 point comparative dissolution media, pH
parameters to profile (USP Apparatus I or II) rpm speed
mimic reference [ADJUSTED FORMULA] paddle or
drug basket for a
dissolution 1:1
values correlation
Full IVIVC study
(Final Formula)
(6 or more subjects)
Deconvolution calculations
(Wagner-Nelson)

CHECK FINAL FORMULA Level

Comparative Dissolution Profile A?
(make minor formula or process
adjustments to reference drug)

TO COMPARATIVE BIOEQUIVALENT STUDY

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 International Journal of Generic Drugs

CHOOSING & USING

THE LEVELS
LEVEL A - ['Concentration Profile']

A MULTI point-to A mathematical model that predicts the Normally a linear

-point evaluation relationship between invitro and invivo curves. relationship is
between an The dissolution profile and the plasma drug developed.
invitro dissolution Scaling factors
concentration profile evaluated mathematically permissible
profile and an
invivo dissolution The most useful and
profile informative level

LEVEL B - ['Time Profile'] Uses

Statistical
moment
NOT a point- A mathematical model that predicts relationships analysis.
to-point between invitro and invivo time courses. CANNOT
correlation discriminate
Compares the mean invitro dissolution time and
between
mean invitro dissolution time (or rate constant) different invivo
The least useful curves with the
informative level same mean
residence time

LEVEL C - ['Single Point']

DOES not
A SINGLE point- show the
to point Establishes a single point relationship between a single shape of the
evaluation dissolution parameter (say a 4 hr assay ) and a single plasma
between an invitro concentration
invivo parameter (i.e. AUC , or Tmax, or Cmax) time curve
dissolution value
and an invivo (CRITICAL!)
dissolution value The most useful
SINGLE point level
Use for pilot and development or
optimization formula/process studies

MULTIPLE LEVEL C - ['Some Points']

DOES not
A One or Two show the
point evaluation Establishes a partial relationship between dissolution whole shape of
between invitro parameter (2 & 4 hr assay ) and some invivo the plasma
dissolution values parameters (AUC , Tmax , Cmax) concentration
and invivo time curve
dissolution values Useful to extend to a (Try Level A)
Level A correlation

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 International Journal of Generic Drugs

ØC H E C K L I S T ×
CL # HPGD-04-Y2K

CR FORMULA DEVELOPMENT
‘…Systematically compare your developing product to the chosen RLD
at all key stages…'

1. Has the Reference Listed Drug (RLD) been chosen from the Orange nYes nNo
Guide?
2. Has the RLD been purchased in all the proposed marketing sizes ? nYes nNo
3. Have different batch numbers (3 lot #’s) of the RLD been purchased? nYes nNo
4. Confirm if the RLD is of recent manufacture (analyze new samples)? nYes nNo
5. Conform that at least 10-20 samples of each RLD lot # and pack size nYes nNo
are available for physical, chemical (assay and impurities), dissolution
and stability testing?
6. Confirm if the RLD has been placed on stability at 40o C for 3 months nYes nNo
for evaluating potential degradation and impurity levels?
7. Confirm if the impurity profile of the RLD has been evaluated? nYes nNo
8. Has reverse engineering of the RLD formula been performed? nYes nNo
9. Have the release and non release controlling excipients (maximum nYes nNo
amounts) been crossed checked in the IIG? (especially for unique or
unusual release controlling excipients)?
10. Are the release and non release controlling excipients compatible nYes nNo
for oral dosage form use (composition and strength)?
11 Have the RLD formula been reviewed in the International Drug nYes nNo
Compendia (Italian, French, Swiss) for formula composition data?
12. Has the FOI system been used to gather data on the Innovative nYes nNo
drug (e.g. Summary Basis of Application)?
13. Has a full analytical profile range been determined from analysis of nYes nNo
the various batch lots of the RLD (at least 3 lots #’s for Assay; Content
Uniformity; Impurities and Dissolution Profile range)?
14. Has the chosen RLD undergone stress testing to establish the level nYes nNo
of its degradation products?
15. Has a multipoint dissolution of the several RLD batch lots been nYes nNo
evaluated to assess the consistency of the RLD's dissolution
parameters?

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 International Journal of Generic Drugs

ØC H E C K L I S T ×
CL # HPGD-04-Y2K

DEVELOPING CR FORMULA
‘…combine the development stages into an overall 'Development Report'
- what did you really do?…’

16. Confirm that the analytical dissolution method (UV/HPLC) has been validated nYesnNo
before comparative dissolution profiles (CDP) are performed?
17. Reject early CDPs using non-validated dissolution assays? nYesnNo
18. USP apparatus I (basket/100rpm) or II (paddle/50-75rpm) is the preferred nYesnNo
dissolution method? Note: basket speeds generally higher than paddle speeds.
19. USP apparatus III (reciprocating cylinder) or IV (flow through cell) may be nYesnNo
utilized for some ER formulation?
20. Water or buffered solutions (NMT pH 6.8) are appropriate dissolution media? nYesnNo
21. Poorly soluble drugs may have an solubility enhancer added to the dissolution nYesnNo
media (1% sodium lauryl sulfate)?
22. Non aqueous and hydroalcoholic (ethanol or IPA) are not/rarely recommended nYesnNo
or appropriate dissolution media for IVIVC?
23. A 12 point dissolution profile is normally always required? nYesnNo
24. Dissolution profile RSDs or coefficients of variation (CVs) should be well under nYesnNo
10%. Target value around 4 - 6% RSD?
25. Four to Six sampling time points should be selected to define an adequate nYesnNo
dissolution profile range e.g. (0, 4, 8, 12, 16, 20hr. / or / 0, 2, 4, 6, 8 hr.) ?
26. Twelve (12) individual dosage units per batch/lot and six (6) sampling points is nYesnNo
the ideal dissolution profile set-up?
27. Examine the RSD per sampling point to evaluate formula/process homogeneity. nYesnNo
28. Develop the IVIVC in the fasted state, study (cross-over human subject study)? nYesnNo
29. Initial pilot studies for end-formula development (final release controlling nYesnNo
excipient optimization) require only 1-3 subjects? - alternatively use…
30. Confirmation IVIVC at final formula stage, requires 6 or more subjects? nYesnNo
31. Use Level C for an initial formula development guide - 3-6 subjects? nYesnNo
32. Use Level A for final formula confirmation studies with 6 or more subjects? nYesnNo

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 International Journal of Generic Drugs

STANDARD OPERATING
PROCEDURES
SOP # HPGD-02-Y2K

CR FORMULA DEVELOPMENT

The following selected model Standard Operating Procedures are recommended for
a generic development unit:

DEVELOPMENT SOP
HPGD-02-Y2K Setting up a General Development SOP.
HPGD-02-Y2K Setting up a Product Specific Development SOP.
HPGD-02-Y2K Contents of a Development SOP - Oral CR Tablets.

DEVELOPMENT FORMULA
HPGD-02-Y2K Vendor Certification Requirements for Product Development.
HPGD-02-Y2K Formulation of CR / ER1 ANDA Oral Tablet Preparations
HPGD-02-Y2K Establishing an IVIVC in Extended Release Oral Dosage Forms).
HPGD-02-Y2K Standard Procedures for Generic CR Product Development

DEVELOPMENT REPORT
HPGD-02-Y2K SOP for Development Reports.
HPGD-02-Y2K Contents of a Development Report - Oral CR Tablets.
HPGD-02-Y2K Parameters for Process Optimization and Process Qualification.

NOTE ON DEVELOPMENT
The intent and purpose of the pivotal batch is as a final demonstration that the
formula, process and controls are well developed and tested during development
stages and really need no significant changes or further process qualification.
However scale-up changes can take place within the SUPAC MR rules after
manufacturing the pivotal batch. These SUPAC MR rules govern the Scale-Up from
pivotal (10% or more) to commercial (100%) and Post-Approval Changes i.e.
changes after registration approval has been given.

ER1 Extended Release Dosage Form: A dosage form that allows a reduction in
dosage frequency as compared to that presented by conventional dosage forms
such as a solution or an immediate release dosage form
[End of Document]

Edition No. : Effective Date: APPROVED:

APPROVED
01
Ed. Status New DD/MM/2000 ___________ ____________ ___________ _________/_________
Department RD RA QC / QA

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 International Journal of Generic Drugs

From Pre-formulation to End Formula

‘research and evaluate the CR formula thoroughly’

Overview of Product Development Stages for a Modified Release Drug Product

Literature search: Under the section titled 'Prescription

P reliminary activities in a drug

development project start with a
comprehensive review of
and OTC Drug Products - Patent and
Exclusivity Data', the patent number
and patent and exclusivity expiration
authoritative reference books on the dates are obtained. The latest
pharmaceutical and analytical cumulative index to the Orange Book
parameters and attributes of the chosen may be viewed on the FDA home page.
drug. Reference works such as the US Use patents (i.e. therapeutic uses) are
Pharmacopoeia, (and supplements) indicated with the symbol "U" followed
B.P., (and addenda) Ph. Eur.; by a number representing a specific
Pharmacopoeial Forum, Physician's therapeutic use. A corresponding list of
Desk Reference; Martindale; Merck; therapeutic uses are given.
Florey; and Vidal are thoroughly Exclusivity information for a specific
reviewed on physical and chemicals category is indicated by an abbreviation
aspects of the active ingredient and followed by the date on which the
potential formulations. An extensive exclusivity actually expires (NCE - Dec
computerized online search relating to 30, 2000) NCE = New Chemical Entity.
the specific drug substance and the
drug product is conducted. Sourcing of Raw Material:
Sourcing for a potential suppliers of the
The USP Supplements and BP active material.
Addenda are carefully screened for new At least two approved suppliers of
monographs at regular intervals during active material should be qualified.
the ongoing drug development program Request samples from potential
as a new active monograph may be
suppliers. Exercised care that the
published during the actual product
active material samples received
development stages.
always represent a production batch
Finally the Innovator's Summary Basis
and are not from an experimental batch
of Approval is obtained via the Freedom
lot where the specifications, physical
of Information Services for data review.
(bulk density and particle size) and
Patent Evaluation: chemical (impurity profile), may change
The Innovator's overall patent situation with time.
is thoroughly evaluated with special Once a suitable active supplier has
reference to product and use patents. been located sufficient material should
Exclusivity and Patent data is reviewed be ordered to allow for preliminary pre-
in the FDA's Orange Book "Approved formulation development to begin prior
Drug Products with Therapeutic the full analytical testing of the
Equivalence Evaluations" Edition 20 (2000) suppliers sample.

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 International Journal of Generic Drugs

This is a time saving device as a full Limited information on the presence of

analytical profile (with BET, specific excipients can be obtained
polymorphism evaluation etc.) may take from microscopic observation. For
one or two months to fully appraise. example, the pharmacognosy of
Testing of Active Material Avicel™ and different starches have
very specific shapes and are thus easily
Sample: identified.
Initiate chemical evaluation with the
analytical development laboratory as Dissolution Profile
per official pharmacopoeia monograph Perform a 12 tablet dissolution profile
(Pharmacopoeial Forum method, if using USP monograph / FDA method or
present at time), or alternatively by the in-house method (which ever is
supplier's test method or a modified in- available at the time of testing).
house analytical method based on the
supplier's method and specifications,
First batch of Active Material:
where no official monograph exists. Active Material Release
This initial active material lot is
Marketing input requirements: released by the Development (or plant
Based on the Innovator's product QC laboratory if the material is intended
obtained from the market place the for pivotal batches), according to
following product presentation pharmacopoeia, (or in-house methods
information is acquired; and specifications in the absence of a
◊ tablet shape, (possible patent on a pharmacopoeia monograph). Release
special tablet or caplet shape.) of material without full monograph
◊ tablet color - individual color for each testing is allowable if the material is not
dosage strength intended for a Process Qualification
◊ proposed code / symbol or lettering (PQ) and pivotal batch.
for punch embossing Physical Characterization of
◊ proposed packaging sizes (smallest; Active:
intermediate; and largest pack sizes)
◊ Container - closure types. (glass,
A full analytical evaluation of the
plastic securitainer, blister pack.) approved supplier active material is
now undertaken that will finally end in a
Innovator's Tablet Testing: comprehensive Analytical Development
Physical Testing Report.
Physical tests evaluating the Standard physical parameters for
innovator's product for tablet color, evaluation are:
weight, thickness, hardness range,
n Polymorphism (TGA / DTA)
friability, etc. as well as an evaluation of
the tablet punch diameter (round) and n Polymorphism (DSC - Calometery)
shape (caplet) are now undertaken. n B.E.T. surface analysis
Inactive Ingredient Identification n IR Solid State / X-Ray Diffraction (XRD)
Evaluation of excipients used in n Particle size distribution
innovator's product are obtained partly n Particle size distribution method
from the package insert, and / or the
n Bulk density
PDR with supporting analytical and
microscopic tests confirming, where n Microscopic morphology
possible, the identification of the n Crystal habit
excipients morphological characteristics
n Solubility (different pH levels,25oC)
and crystal shapes.

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 International Journal of Generic Drugs

Physico-Chemical: ⇒ Physical properties of tablets:

• Optical rotation ♦ Weight
• Enantiomeric purity
• O.V.I. testing (organic volatiles) ♦ hardness
• Impurity profile ♦ thickness (core & coat)
♦ friability, dissolution etc.
Evaluation of raw material
supplier: Choice of Punch and Die Set:
• DMF availability Ordering of punches
• Compliance with USP monograph The Pivotal Batch as well as the
Process Qualification batch should be
• Impurity profile and stability profile
compressed on a production (or
• Commitment to maintain written production type) machine, e.g.
physical / chemical specifications Manesty™ Fetta P1200™; Kilian
• Statement of non-patent infringement RTS™
Production supervisors are consulted
Interim analytical and pre- regarding the choice of the
formulation development report: compression machine. Avoid any
The findings of the initial development manufacture with worn-out punch and
work are summarized and tabulated die sets. The Punch Supervisor initiates
into an interim development report, the ordering of the embossed or scored
covering the analytical and pre- punch and die sets suitable for the
formulation findings that will eventually proposed marketed product. Scoring is
form part of the overall comprehensive important. Tablet shape and scoring
product development report. can affect the dissolution parameters.
DEVELOPMENT LOTS Maintaining the proposed marketing
Developing the formula through a tablet shape is an important factor at
series of mini experimental trials the dissolution profile evaluation stage.
involves evaluating the type of Analytical testing of tablets /
granulation process and the physical caplets:
properties of the granules / tablets
Dissolution in USP medium and other
formed. Steps for the choice of a
relevant media versus innovator's
suitable process are:
product as well as the Uniformity of
♦ Evaluation of suitable excipients: Content for low drug active
♦ Excipient compatibility using DSC concentrations are two critical
method and 55o C stability. development parameters. Refer to the
♦ Dry mixing, slugging, milling (dry USP requirements for Uniformity of
granulation procedures) Content vs. uniformity of dosage units,
where the active content is above or
♦ Wet granulation (by low / high shear below 50 mg.
mixer or F/Bed sprayer), etc.
♦ Determination of granule moisture Active Stability:
content (~1-3%) and temperature Ordering of raw material for Process
setting for testing LOD. (Mettler™,/ Qualification (PQ) and Pivotal Batches.
Computrac™ Infra Red Dryers etc.) On accepting the stability profile data
from the active material evaluation,
⇒ Physical properties of granulate:
coupled with the results the from the
n Flow
development lots, the active supplier is
n density now approved. Order sufficient material
n compressibility. for the PQ and Pivotal Lot manufacture.

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 International Journal of Generic Drugs

It is important to use same batch of work are summarized in an interim

active material for the PQ and Pivotal process report, outlining the
batch, as these two batches are optimization data for final presentation
somewhat complementary to each other in the product development report.
and form the culmination of the formula PROCESS QUALIFICATION
and process development. (The PQ Batch)
An average of 2-3 months may be The process qualification batch is
required from date of order to receipt of manufactured in order to detect any
approved active material, during this problems that may arise during the
period process optimization batch(es) manufacture of production size batches,
and scale-up work is performed. permitting a timely solution before the
PROCESS OPTIMIZATION manufacture of a pivotal batch.
The process qualification team and
Process optimization is the process of
production personnel should discuss
fine tuning the manufacturing process
formula and process instructions and
and making minor adjustments to the
decide on optimum batch size, and then
formula or process. It should be
define critical processing steps and test
performed on a larger batch size so that
parameters to be evaluated.
the potential problems of scale-up can
be addressed, as they arise with larger Master Documentation:
size manufacturing equipment that use The project researcher finalizes the
the same operating principle. Fine tune Batch Formula and Manufacturing
the effects of granulation and Instructions documentation package for
compression parameters may include; signing by the authorizing personnel.
The process qualification team
♦ granulation speeds (i.e. blade
prepares the PQ Protocol and consults
speeds (i.e. chopper 1 and II in high
with the analytical coordinator with
speed Granulators -e.g. Diosna™ )
respect to the analytical testing
♦ number of mixing stages (one or two requirements of the many PQ samples.
for high shear mixing) Production personnel are present
♦ mixing times and overall mixing during the process qualification batch
run, as this process usually mimics
♦ solvent amounts and rate of addition
production conditions and acts as a
♦ screen size of granulate (e.g. 0.6-0.8 precursor to the upcoming pivotal
mm) with respect to tablet properties. batch. The suitability of the process
♦ Drying temperature versus LOD documentation package is evaluated
obtained and its effect on granulate during this run. Amendments are added
and tablet properties (capping, flow, where necessary to effect practical
sticking, and hardness). documentation for the pivotal batch.
Upon completion of the process
♦ Blending times (short) - the effect on qualification batch testing, a Process
uniformity, lubricity and dissolution. Qualification Report is formulated.
♦ Effect of hardness on tablet
properties (aging, dissolution,
ANALYTICAL TEST METHODS
friability, hardness limits ). FINALIZED
A fully validated stability indicating
♦ Qualify the Hardness Range Limits assay and impurity profile is finalized
♦ Final evaluation of stability profile. prior to executing the pivotal batch. The
Process Optimization Report: analytical methods need to be
The findings of the process optimization authorized and signed prior to the date
of the actual pivotal manufacture.

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 International Journal of Generic Drugs

biostudy protocols on specific drug

PIVOTAL LOTS products on the FDA CDER home page.
Based on the PQ batch results and W here possible consult these protocols
amended documentation, the pivotal lot with care prior to the bioequivalence
is now prepared. In the manufacture of evaluation.
the Pivotal Batch, a minimum of 100 Pivotal Sampling & Testing
000 (net) dosage units are required. The sampling and testing procedures for
Some firms prepare documentation for the pivotal batch hold a special regulatory
100 000 dosage units gross, ignoring significance. The pivotal batch represents
the fact that there may well be 2% to the documented batch that is filed with
5% production losses. The net batch the FDA's Office of Generic Drugs, as well
yield turns out to be 98 000 or 95 000 as being the batch representing the
dosage units well below the 100 therapeutic bioequivalence of the drug
thousand net required by FDA’s Office product when compared against the
of Generic Drugs (OGD). reference listed drug (RLD) or the
It is prudent to scale the pivotal batch for innovator's own drug, during the biostudy.
at least 120 000 dosage units. Under these circumstances, the need for
Remember the pivotal batch may range a fully representative sampling and
from 10% net to 100% (i.e. full size) of the testing procedure, as required by GMP, is
proposed commercial batch size. achieved by a specific written 'sampling
and testing' protocol.
Experienced Generic firms who do not
This special batch has both legal and
anticipate any problems with the pivotal
regulatory aspects in the eyes of the FDA
documentation often target the pivotal
- sampling must not only be done but
quantity to 70% of the proposed
seen to be done (i.e. via a well written
commercial lot thus achieving appropriate
protocol).
scale-up and pivotal in a single batch.
DEVELOPMENT REPORTS
Packing the pivotal batch. Firms should have a well structured and
The Pivotal batch needs to be fully assembled Product Development Report.
packed in the proposed marketing packs Although not a FDA 21 CFR regulatory
(OGD rules). Frequently the pivotal batch requirement, a functional Development
is packed into 2, 3 or 4 different pack Report will certainly go a long way to
types and several different pack sizes convince the reviewers of a fully justified
and closure combinations. (combinations overall process that consistently produces
of glass, HDPE, Clicloc™, plastic, metal the desired end-product.
caps, or Al foil/blister packs etc.)
The Development Report is the basis on
The tablet trail documentation identifies
which the validation protocol is designed
the exact quantity packed into each
and structured, without it validation may
container-closure system. The overall
well be incomplete or problematic.
packaging should total to 100% of the net
pivotal batch. Development reports are required to be
At least 15-20 % of the exhibition (pivotal) seen by the site inspectors at the product
batch should be packed into each specific pre-approval inspection (PAI
container-closure category. visit). The preparation of a Product

IVIVC FIRST THEN BIOSTUDY Development Report should be based

Bioequivalence evaluation on all the interim reports prepared
The pivotal batch samples are used to during the development work, including
perform the bioequivalent study after an analytical reports and where well
IVIVC has been estimated. The FDA prepared, assembled and structured - oil
displays a list of about 5-6 model the review process - immeasurably.

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 International Journal of Generic Drugs

Locum International Publishers

ISSN 0793 8713 - ISSN 0793 8721 Handbook of
A Series Publication in association with
The International Association of
Generic Drug Manufacturers. Pharmaceutical
Generic Development
NEW Edition ISBN 965 492 004-2
Year 2000

Oral
Part ONE
DRUG Development Know-how
&
Part TWO
Suspensions
ANDA Development Technology

Drug Development The Handbook of Pharmaceutical Generic

Development is an essential workbook covering
the full CMC & Bio and RA sections of normal
Oral Suspension ANDA / AADA and a
Suspension for Reconstitution.
Part One (Development ISBN 965 492 004-2)
and Part Two (ANDA Development - ISBN
965492005-0 with detailed commercial and
state-of-the-art formula) provides essential
know-how technology on all aspects of;
ANDA Development Development, Formulation, Scale-up,
Process Optimization & Qualification;
Pivotal and large scale Validation batches;
analytical, cleaning and process validation;
essential documentation and OGD
regulatory know-how that is essential for a
Cephalosporins successful review for a FDA approval,
Synthetic Penicillins saving queue-time and money.
Essential development know-how on Oral
Azithromycin Suspensions and Suspensions for
SMX-TMP Reconstitution professional developers to
(Cotrimoxazole) understand the nuts-and-bolts on Generic
MODIFIED RELEASE DEVELOPMENT with a
high-tech detailed ANDA development to
produce flawless files. (Print & CD ROM).
Presented at an Advanced Technological Level.
Visit Web Secure Book Shop or Fax+972-97-494 532
Locum Publishing House PO Box 16075
Arlington VA 22215-1075 USA [email protected]
Fax Int: +972-97-494 532 / US+(1) 435-808-1891 A Locum House Publication ©Copyright LOCUM 1995 - 2000

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 International Journal of Generic Drugs

PRODUCT DEVELOPMENT GUIDE

CONTROLLED RELEASE DOSAGE FORMS
PRE-FORMULATION
Introduction
Guidelines for the development of a controlled release product primary for the US market,
Note: some tests or procedures may be unnecessary for certain products. The order of
performing the various stages may change depending on the product under development.
These guidelines may be modified for other geographic zones.
Development Scope of Product Development Stage
Stage 1 Literature Search
Literature Research USP BP Pharm. Eur, PDR, Martindale, Merck, Florey, Vidal
FDA - FOI Summary Basis of Approval
On-linecomputerized Electronic Data Base (articles and publication on test methods,
search Dissolution synthesis procedures, drug impurities,
pharmacokinetics and dynamics)
FDA CDER Evaluation of Biostudy parameters, Dissolution methods.
Patent evaluation Orange Guide + FDA CDER WWW Patent Consultant
Stage 2 Active Sourcing
Sourcing for Active International Suppliers US, European Asian E.g. Lek (Czech) ZIP,
Raw Material Esteves, (Spain); (Mohrs Spain) (S.I.M Italy)
Review Suppliers Catalogues
Potential Suppliers List Request samples and C of A and Specifications
Evaluate at least two suppliers fully.
Stage 3 Active Evaluation
Evaluate Potential Evaluate at least two to three potential active suppliers
Actives • DMF availability
• Compliance with USP monograph
• Impurity profile and stability
• Potential Polymorphic / solvate forms
• Commitment for physical specifications
• Statement of non-patent infringement
Stage 4 Active Purchasing
Purchase (Potential) Evaluate at least two potential active material suppliers for
Active Material approved supplier status
Stage 5 Active Testing
Testing of Active Chemical testing by the R&D analytical lab as per
Material sample a. Pharmacopoeia monograph (if present)
b. Pharmacopoeia Forum (if available)
c. In-house method (based on manufacturer)
d. Supplier's test methods and specifications

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 International Journal of Generic Drugs

FORMULATION
Development Scope of Product Development Stage
Stage 6 Innovator's Product Purchasing
DRUG PRODUCT Purchase at least 3 different lots in smallest and largest pack size
Innovator Samples for each product strength
Stage 7 Innovator's Product Testing
Innovator Testing Evaluate physical parameters:-
Tablet shape, tablet color, code for punch embossing, pack sizes
containers materials, closure types; cotton and desiccants.
Innovator Physical Physical testing
Testing Weight; Thickness; Hardness; LOD; Friability; Disintegration:
Evaluation of tablet punch; size; score; embossing and shape
Evaluation of Innovator Summary Formula in PDR; International PDRs (Italian, French,
formula ingredients Swiss) and Innovators product's insert (obtain latest FOI -FDA)
Perform actual analytical testing on innovator's product
Microscopic Particle/crystal information on:-
observation • Particle size
• Crystal shape, habit,
Differentiation on the presence of specific excipients can be
verified from microscopic observation. E.g., Cross-linked
cellulose's Starch and Avicel have a specific shapes and
morphology
Evaluation of Biostudy Review FDA CDER Home page for listing and Biostudy
parameters parameters
Developing a meaningful IVIVC on a product -by-product-basis
Dissolution profile USP monograph and FDA method - (where present)
IVIV Correlation Dissolution; 12 unit Dissolution Profile
Stage 8 Bulk Active Testing
FIRST BATCH FROM Physical characterization of bulk batch
APPROVED • Polymorphism
SUPPLIER • B.E.T.
Full Physical • Particle size distribution (& method development)
characterization • Bulk density;
• Microscopic observation
FULL CHEMICAL Chemical characterization
CHARACTERIZATION • Assay
• Stressed Analysis
• Degradants (Expected)
• Impurity profile
• Optical rotation
• Enantiomeric purity
• O.V.I. Testing

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DEVELOPMENT BATCHES
Development Stage Scope of Product Development
Stage 9 Excipients
Evaluation of Choice of Releasing and Non-releasing controlling excipients
formulation with Evaluating predictability models.
suitable excipients Excipient compatibility using DSC methods and stability
assessment
Choosing dissolution parameters (sampling times and percentage
dissolved ranges)
Determining several dissolution profiles during formulation;
optimization; final formula & process qualification
Stage 10 Container Closure System
Evaluation of suitable Choice of container-closure-liner system including:
Container-Closure • material composition,
System • type of thermoplastic resin and resin pigments,
• manufacturers and suppliers,
• liners and seals used by closure manufacturer,
• cotton and desiccants.
• manufacturer's DMF numbers for all component parts
• Letters of Access for regulatory authorities to view DMF dossiers
Stage 11 Manufacturing Process
EVALUATION • Wet granulation (aqueous or non aqueous)
SUITABLE high shear mixing / low shear mixing
MANUFACTURING • FBD spray procedure), or
PROCESSES • Dry mixing, dry granulation and/'or Slugging
• Determination of order of mixing
Wet Granulation • Determination of pre-mixing (in Granulator)
Dry Granulation • Determination of fluid addition (spray rates, if relevant)
Slugging and Dry • Determination of granulation time (chopper I & II)
Granulation • Determination of torque end-point value
• Determination of Drying parameters
• Determination of LOD limits
• Determination of testing temperature for checking LOD limits
(State machine used e.g. Mettler™, Computrac™).
GRANULATION • Flow properties
Physical Properties of • Density, (bulk; tapped)
Granulate • Particle-size distribution
• Compressibility (Carr's Compression index)
Compression • Weight, • Hardness,
Physical Properties of • Thickness, • Friability
Compressed Tablets • Disintegration • Dissolution
Final Formula Assessment of Final Master Formula and accelerated 1-3 month
Established stability profile

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 International Journal of Generic Drugs

ACTIVE PURCHASE
Stage 12 Bulk Active Purchased
Active material Ordering of Active material for Process Qualification (PQ) and Pivotal
Bulk purchase Batch(es). On approval of final formula, order sufficient material for
the PQ (2) and Pivotal Lots (sufficient for all strengths and batch
sizes). NB: Never active mix batch numbers in PQ & Pivotal Lots.
FULL LABORATORY EVALUATION
Development Scope of Product Development
Stage 13 Analytical Evaluation
Analytical testing of • Dissolution - in USP medium (Multipoint profiles) and other relevant
tablets/Caplets media versus Innovator's product.
• U of C-for low active concentrations. Refer to USP requirements for
uniformity of content vs. uniformity of dosage units.
Dissolution • Validation Of Dissolution Method; With Choice Of All Discriminatory
Validation Dissolution Parameters (Usp Type; Media; Ph; Agitation) Completed
Prior To Process Optimization And Process Qualification
NOTE: Dissolution parameters (as above) may well be adjusted to
establish a Level A or C correlation after IVIV study
Validation Package • Validation of analytical package i.e. Assay; Dissolution ; Content
Uniformity completed prior to Process Qualification
PROCESS OPTIMIZATION
Development Scope of Product Development
Stage 14 Process Optimization
GRANULATION ◊ Effect of granulation parameters
OPTIMIZATION ◊ Granulation time,
◊ Speed of choppers (I & II) or mixer blades
◊ Solvent addition rate and overall amount
◊ Ratio of intra-granulate Disintegrant and binders agents
◊ Screen size for milling (e.g. 0.6 or 0.8mm)
◊ Evaluation of optimized granulate and tablet attributes
DRYING ♦ FB Drying temperature vs. target LOD and range limits. Effect on
BLENDING granulate and tablet properties (re: flow, capping, sticking).
COMPRESSION ♦ Blending times
♦ Lubricant Split into two parts (pre-blending and final blending)
♦ The effect on Content Uniformity, Granule lubrication and
Dissolution profile.
♦ Evaluation of unit dose sampling vs. Content Uniformity.
♦ Effect of hardness on tablet - aging, dissolution, friability.
♦ Evaluation of Hardness Range Limits
♦ Evaluation of stability results of optimized mfg. process.
PROCESS Prepare PO Report. This Process Optimization Report forms part of
OPTIMIZATION the product Development Report. Dissolution Report included.
REPORT

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DISSOLUTION PROFILING
Development Scope of Product Development
Stage 15 Analytical Evaluation
Analytical testing of • Dissolution - in USP medium (Multipoint profiles) and other
tablets/Caplets relevant media versus Innovator's product.
• U of C-for low active concentrations. Refer to USP requirements
for uniformity of content vs. uniformity of dosage units.
• Validation of analytical package i.e. Assay; Dissolution ; Content
Uniformity completed prior to Process Qualification
ESTABLISHING AND INVITRO INVIVO CORRELATION
Development Scope of Product Development
Stage 16 Analytical Evaluation
• Dissolution - in USP medium (Multipoint profiles) and other
IVIV Correlation relevant media versus Innovator's product.
• Perform IVIV Bioavailability Study
Establish a Level A or C correlation without adjusting dissolution
parameters and time scale
• Adjust the dissolution parameters or time scale to achieve a
Level A or C correlation (adjust only if necessary)

SCALE UP
Development Scope of Product Development
Stage
Stage 17 Scale-up
Scale-up Scale-up lot prepared if larger batch size scale up problems
anticipated.
Process Qualification batch and Scale-up batch may be evaluated
as a single batch.
Scale-up Report The preparation of a Scale-up Report. The Scale-up report forms
part of the overall Development Report

PROCESS QUALIFICATION
Development Scope of Product Development
Stage
Stage 18 Process Qualification (PQ)
The process qualification batch is manufactured in order to detect any problems that may
arise during the manufacture of production size batches, allowing a solution prior the
manufacture of the pivotal demonstration batch. Scale-up to the pivotal batch size or 70% of
the pivotal batch may be combined with qualifying the manufacturing process At this stage
full manufacturing documentation is prepared alone standard procedures.

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PROCESS QUALIFICATION
Development Scope of Product Development
Stage
Stage 18 Process Qualification - (Continued)
PRODUCTION Process Qualification batch should be compressed in a production
FACILITIES (production type with same principle & operation) tabletting
machine
BATCH SIZE Size of pivotal and marketing batch confirmed (NLT 100 000 net/
packed at target parameters or 10% of proposed market batch).
BATCH Preparation of Master Formula and Processing Instructions
DOCUMENTATION Discussion of formula, manufacturing process and control
parameters with production personnel and QA Staff
FINAL REVIEW and Review of proposed formula, manufacturing process and control
AUTHORIZATION parameters with production personnel and QA Staff with
authorization signatures (RD; QA-QC; RA; and Production)
PROTOCOL PQ. protocol prepared
KEY STEPS Critical manufacturing steps designated; sampling and testing
parameters specified.
OPERATING Presence of production and control personnel during PQ
CONDITIONS manufacture
DISSOLUTION 12 POINT DISSOLUTION profile of PQ batch.
PROFILE
PROCESS Upon completion prepare P-Q Report. This P-Q report forms part
QUALIFICATION of the overall Development Report
REPORT
PIVOTAL BATCH
Development Scope of Product Development
Stage 19 Pivotal Production
PRODUCTION Pivotal batch MUST be compressed in a production tabletting
FACILITIES machine (or production type with same principle and operation)

BATCH Preparation of FINAL Master Formula and Processing Instructions

DOCUMENTATION
REVIEW and Review of FINAL formula, manufacturing process and control
AUTHORIZATION parameters with production personnel and QA Staff. Pivotal
authorization signatures (RD; QA-QC; RA; and Production)
attached.

OPERATING Operation of production and control personnel during Pivotal

CONDITIONS manufacture, aided by development team.
The preparation of a Pivotal Report. This pivotal report forms part
of the overall Development Report.

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 International Journal of Generic Drugs

BIOEQUIVALENT STUDY
Stage Scope of Product Development
Stage 20 BIOSTUDY Evaluation
BIOSTUDY Perform Food Effect AND Fasted Biostudy on Pivotal Lot Samples
HIGHEST DOSAGE Biostudy generally performed on highest strength of product
TWO STUDIES Food Effect AND Fasted Study required for CR/MR/ER forms
WAIVER For multiple strength CR products Invitro dissolution testing
CONDITIONS conducted in three different pH media on lower dosage forms
SIMILARITY TESTING Perform Similarity Test [F2 Test] on dissolution results

PRE-SUBMISSION AUDITING
Stage Scope of Product Development
Stage 21 ANDA Pre-Submission Auditing
Development Report Audit all raw data supporting Development Report
ANDA Regulatory File Audit Plant and Laboratory Documentation as per ANDA
SOPs Review SOP System and Update level
CGMP Review cGMP of Manufacturing Processes
Validation Protocol Product Process Validation Protocol complete and signed
Biostudy Report Evaluate and develop a IVIV correlation (Level A where possible)

ANDA SUBMISSION
Stage Scope of Product Development
Stage 22 ANDA Submission
ANDA Submission Submit ANDA after thorough in-house audit review
Biostudy Section 6 (Separate File)
(9 Copies - as per Color system)
(1 Field Copy)

VALIDATION BATCHES
Stage Scope of Product Development
Stage 23 Process Validation
Protocol Process Validation Protocol for 3 consecutive marketing lots
Execute validation Process Validation of 3 consecutive marketing lots
Report Process Validation Report
Similarity Show intra-batch similarity
Bio-Validation Show inter-batch similarity between Biobatch (Pivotal) and the
Similarity Commercial Validation Lots

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 International Journal of Generic Drugs

COMMERCIAL RE-VALIDATION DUE TO MAJOR CHANGE

Stage Scope of Product Development
Stage 24 Process Re-validation
Formula Change Revalidate procedure with new formula process or equipment with
Process Change a different operating principle
Equipment Change Follow SUPAC MR Rules Level I, II or III
Minor change Follow SUPAC MR Rules Level I

IMPORTANT NOTE ON DEVELOPMENT

Developers are encouraged to develop IVIVC for CR/ER dosage forms in the
expectation that the information will be useful in establishing dissolution
specifications and will permit certain post approval formulation and manufacturing
changes without additional bioequivalence studies.
The objective of developing an IVIVC is to establish a predictive mathematical model
describing the relationship between invitro dissolution settings and the actual invivo
drug-plasma parameters found, (AUC, Cmax, Tmax).

The invitro dissolution settings are adjusted (via media, pH agitation) until a I : I
correlation is achieved (Level A) or a single dissolution point and a plasma
parameter is shown to correlate (Level C). When more than one point correlates a
multiple Level C is obtained - which may possibly be upgraded to a Level A with
additional work.
This matching of dissolution settings with plasma levels, that are derived from a
specific CR formula and its corresponding manufacturing process, is in fact simply
an arbitrary set of values that establish the so called 'predictive mathematical model'.

An IVIVC should be evaluated to demonstrate that predictability of the invivo

performance of the drug product (plasma parameters) from its in vitro dissolution
characteristics (equipment settings) is maintained over a range of dissolution
release rates and manufacturing changes.

DEFINITIONS.
MR Modified Release Solid Oral Dosage Forms include both delayed and extended release
drug products

ER Extended Release Dosage Form: A dosage form that allows a reduction in dosage
frequency as compared to that presented by conventional dosage forms such as a solution
or an immediate release dosage form

DR Delayed Release The release of a drug at a time other than immediately following oral
administration

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 International Journal of Generic Drugs

STANDARD OPERATING Page 1of 1.

PROCEDURES
SOP # HPGD-02-Y2K

CR FORMULA DEVELOPMENT

The following selected model Standard Operating Procedures are recommended for
a controlled release development unit:

DEVELOPMENT SOPs
HPGD-02-Y2K Setting up a Product Specific ER Development SOP.
HPGD-02-Y2K Setting up IVIVC for Extended Release Oral Dosage Forms
HPGD-02-Y2K Contents of a Development SOP - ER Oral Tablets.

DEVELOPMENT FORMULA
HPGD-02-Y2K Formulation of CR / ER1 ANDA Oral Tablet Preparations

HPGD-02-Y2K Establishing an IVIVC in Extended Release Oral Dosage Forms

HPGD-02-Y2K Standard Procedures for Generic Product Development

HPGD-02-Y2K Establishing a level A IN-VITRO IN-VIVO correlation

HPGD-02-Y2K Establishing a level B IN-VITRO IN-VIVO correlation

HPGD-02-Y2K Establishing a standard level C IN-VITRO IN-VIVO correlation

HPGD-02-Y2K Establishing a multiple level C IN-VITRO IN-VIVO correlation

DEVELOPMENT REPORT
HPGD-02-Y2K Evaluating the predictability of a level A - IVIV Correlation
HPGD-02-Y2K Development and Evaluating of a level C IVIV Correlation

[End of Document

Edition No. : Effective Date: APPROVED:

01
Ed. Status New DD/MM/2000 ___________ ____________ ___________ _________/________
Department RD RA QC / QA

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 International Journal of Generic Drugs

Vitro-In-Vivo
U. of Maryland & IAGIM

Correlations
IVIVC Series Part I
In Vitro In Vivo Correlation Predicted metoprolol concentrations were
with Metoprolol Extended obtained by convolution of the in vivo
dissolution rates. Prediction errors were
Release Tablets Using estimated for Cmax and AUC to determine
Two Different Releasing the validity of the correlation.
Formulations: An Internal An average percent prediction error for
Cmax and AUC for all formulations of less
Validation Evaluation than 12% was found for all IVIVC models.
Author:- Natalie D. Eddington1,2* 1Pharmacokinetics The relatively low prediction errors for Cmax
Bio-pharmaceutics Laboratory 2Department of and AUC observed strongly suggest that
Pharmaceutical Sciences School of Pharmacy, the metoprolol IVIVC models with two
University of Maryland at Baltimore 100 Penn formulations used in development are
Street, AHB Baltimore, MD
21201-6808 (410)706-6710 (410)706-6580-(fax) valid.
Email: [email protected] Previous IVIVC with all three formulations
Summary/Abstract was also found to be valid. The relatively

T he objective of this analysis was

develop and validate internally an
in-vitro in-vivo correlation (IVIVC) for a
low prediction error indicates that the
correlations are predictive when using two
or three formulations, and allows the
hydrophilic matrix extended release associated dissolution data to be used as
metoprolol tablet using a combination of a surrogate for bioavailability studies.
two formulations with different release
rates. Three formulations of a hydrophilic
Introduction
matrix extended release tablet were The process of developing and
manufactured to release metoprolol at a validating an in vitro in vivo correlation
slow, moderate and fast rate. (IVIVC) is playing an exceedingly
The in vitro dissolution methods utilized USP
Apparatus II, pH 6.8 at 150 rpm.
prominent role in the formulation of
extended release products.
Seven healthy subjects received three
metoprolol formulations (100 mg): slow, The development and validation of
moderate, fast releasing and an oral IVIVCs has been discussed extensively
solution (50 mg). over the past 10 years. The focus of
Serial blood samples were collected over the debates center on the processes of
48 hours and analyzed by a validated developing an IVIVC and methods to
HPLC assay using fluorescence detection. assess its validity.
The f2 metric (similarity factor) was used to Even though there are numerous
analyze the dissolution data. examples of IVIVCs in the literature,
Correlation models were developed using many of the correlations have not been
pooled fraction dissolved (FRD) and rigorously tested through a systematic
fraction absorbed (FRA) data from various evaluation of their predictability.
combinations of two formulations
(slow/moderate; moderate/fast and A validated IVIVC allows for the
slow/fast). prediction of the in vivo behavior of
alternative formulations, provided that
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 International Journal of Generic Drugs

the “new” formulation is within a extended release metoprolol

predefined range determined by the formulation.
formulations used to develop the The IVIVC was developed using three
correlation. formulations of metoprolol tartrate as
In addition, the identification of an well as various combinations of the
appropriate dissolution testing system three formulations.
is critical in IVIVC development and According to the Biopharmaceutics
subsequent validation, since it provides Classification System, metoprolol is a
the link between dosage form “Class I” drug, i.e. high solubility and
optimization and the oral absorption permeability.5
profile. In addition, its relatively short half-life
The recent FDA-IVIVC guidance, suggests that it is a suitable candidate
outlines methods of internally and for an extended release formulation.
externally validating an IVIVC along In previous work, we have developed
with the predictive criteria to assess its and validated a correlation for
validity.1 extended release metoprolol tablets
using three different releasing
Internal validation refers to how well formulations.
the IVIVC model predicts the in vivo
behavior of the formulations used to The IVIVC guidance suggests that a
develop the correlation. correlation can be developed with two
or three formulations. The purpose of
External validation focuses on how this work is to assess the ability of
well the IVIVC model predicts the
developing a correlation with
bioavailability of alternative
metoprolol extended release
formulations, which differ from those,
formulations using various
used in the initial correlation.
combinations of two formulations.
The alternative formulations may METHODS
represent changes in release and non-
Formulations. Metoprolol formulations
release controlling excipients,
evaluated in this analysis have been
manufacturing site changes, and
previously described.4
manufacturing process changes or
scale-up of a formulation.
Three formulations were designed to
release metoprolol at a slow, moderate
Previous work in our laboratory has and fast rate. The formulations were
focused on the influence of processing manufactured at the Industrial
changes, excipient changes and scale- Pharmacy Laboratory at the University
up on in vitro dissolution and in vivo of Maryland using hydroxypropyl-
bioavailability.2,3 methylcellulose (HPMC) as the release
Further extension of this work rate controlling excipient.
examined the development and internal The formulations were designed to
validation of a matrix metoprolol release metoprolol at three different
extended release dosage form.4 rates referred to as: slow, moderate
Numerous sustained or extended and fast.
release metoprolol formulations have Dissolution.
been previously developed, however The release characteristics of the slow,
there are limited examples of validated moderate and fast formulations were
IVIVCs for metoprolol. examined using the following
Previously, an IVIVC was developed dissolution testing methodologies: USP
and validated for a hydrophilic matrix Apparatus I, pH 6.8 at 150 rpm.

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Dissolution tests were performed on The dissolution profiles were compared

six tablets and the amount of drug using the similarity factor, f2, presented
released was analyzed in the following equation (1):
spectophotometrically at a wavelength
∑
n
of 275nm. Dissolution samples were
f2 = 50 log{[1+1/n t =1 (Rt - Tt)2]-0.5 x 100]}
collected over a 12 hour period.
Bioavailability Study:
Where Rt and Tt are the percent dissolved at
The Bioavailability Study has been each time point for the reference product and
previously reported.4 This was an open, the test product, respectively.
fasting, single dose, four treatment Using the f2 values, dissolution profiles
crossover study. The health status of were considered dissimilar if these
each subject was based on physical values were less than 50 with the
examination, history, ECG and clinical average difference between any
laboratory tests. dissolution samples not being greater
Nine normal healthy, male and female, than fifteen percent.
non-smoking volunteers were enrolled In Vivo Data Analysis.
in the study and received three Metoprolol concentration-time data was
formulations of metoprolol (100 mg) in evaluated using the Phast program*.
a randomized fashion. In addition, to The bioavailability parameters, Cmax,
the extended release formulations, an Tmax and AUCinf were estimated for each
oral solution (50 mg) of metoprolol subject. (*Phoenix Scientific Software, Version
tartrate was also administered. 2.2, Montreal, Canada) and WINNOLIN Professional
(SCI Software; Cary, North Carolina)
Blood samples (6 ml) were collected at The percent of drug absorbed versus
the following times: 0 (pre-dose) and at
time was determined using numerical
0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,
deconvolution, where the
18, and 24 hours post-dosing. Samples
pharmacokinetic parameters of the oral
were centrifuged for 10 minutes at
solution were used as the impulse
25oC. Each metoprolol administration
function.
was separated by a washout period of
seven days. Pulse rate and blood Correlation Development and
pressure were monitored in each Internal Validation.
subject at least three minutes prior to The data generated in the
each blood sample collection. bioavailability study was used to
The study was approved by the develop the IVIVC.
University of Maryland and the The correlation was developed using
Baltimore Veteran’s Administration mean metoprolol plasma concentration
Institutional Review boards and each vs. time data following the slow,
subject provided informed consent prior moderate and fast releasing
to enrollment. formulation.
Metoprolol plasma sample analysis was The correlation models was developed
performed with a previouly validated using pooled mean FRD and pooled
HPLC fluorescence detection method.6 mean FRA data from the following
Dissolution Data Analysis. combinations of two formulations: (1)
slow and moderate (S/F), (2) moderate
The in vitro dissolution data was
and fast (M/F) and (3) slow and fast
analyzed by estimation of a similarity
(S/F). Linear regression analysis was
factor, the f2 metric7 and parameterized
used to examine the relationship
by the sigmoid Emax model.
between FRD and FRA.

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 International Journal of Generic Drugs

The internal validation was based on The IVIVC was considered valid if the
how well each IVIVC model (S/M, M/F Cmax and AUC prediction errors were
and S/F) predicted the in vivo < 10 percent.1
performance of each formulation (i.e.,
slow, moderate and fast). RESULTS
The in IVIVC model predicted In vitro and in vivo studies.
metoprolol plasma concentration was Profiles of the cumulative metoprolol
determined by convoluting the in vivo fraction dissolved from the slow and
dissolution rate with the moderate (S/M), moderate and fast
pharmacokinetic parameters from the (M/F) and slow and fast (S/F)
oral solution administration. formulations using USP Apparatus I,
The validity of the three correlation pH 6.8, 150 rpm are illustrated in
models (S/M, M/F or S/F) was Figure 1A, 2A and 3A, respectively.
determined by calculating the The associated f2 metrics for the S/M,
prediction errors for the observed and M/F and S/F were found to be 39.26,
predicted Cmax and AUC for each 45.99 and 30.9 respectively, which
formulation to determine the accuracy suggested that the two profiles were
of the IVIVC models in characterizing not similar.
the rate and extent of metoprolol Mean pharmacokinetic parameters are
absorption.
summarized in Table 1.
The percent prediction errors for Cmax Table 1. Mean Pharmacokinetic Parameters after
Extended Release Metoprolol Formulations.
and AUC were calculated as follows:
Formula Cmax Tmax AUCinf
Type (mg/L) (hrs) (mg.hr/L)

(2) - %PECmax Solution 58.6 2.07 346

(13.8) (0.53) (40.6)

[ C max( obs) − C max( pred )  Slow 66.2 4.86 718

=   * 100 (15.4) (1.06) (192)
 C max(obs) 
Moderate 91.0 3.57 810
(32.5) (0.53) (287)

Fast 120 3.14 821

(3) - %PEAUC (31.5) (0.38) (197)

Figures 1B – 3B:-
[ AUC( obs) − AUC( pred )  Present the fraction of drug absorbed
=   * 100
 AUC (obs)  for the slow and moderate (S/M),
moderate and fast (M/F) and slow and
fast (S/F) formulation vs time.
KEY
Where Cmax(obs.) and Cmax(pred.) IVIVC Correlation, Development
= The observed and IVIVC model predicted and Validation.
maximum plasma concentration profiles,
Figures 4A - 4C present the pooled
respectively;
FRD vs. FRA for the S/M, M/F and S/F
AUC(obs.) and AUC(pred.) = The observed and formulations using USP Apparatus I,
IVIVC model predicted AUC for the plasma pH 6.8 at 150 rpm.
concentration profiles, respectively.

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 International Journal of Generic Drugs

The regression lines obtained between An established IVIVC allows for

FRA and FRD for all IVIVC models certain post-approval changes as
were significant (p <0.05) and the described in the Scale-up and Post
slopes were not significantly different Approval Changes for Modified
from 1 (p < 0.05). Release (SUPAC-MR) FDA
The internal validation was performed Guidance.8
by convolution of the (S/M, M/F and Further, a valid IVIVC allows for the
S/F) dissolution data that corresponded use of dissolution data in place of
to each formulation (S/M/F). Each of additional bioavailability studies.
the IVIVC models predicted metoprolol Theobjective of this analysis was to
plasma concentration versus time assess the development and validation
profiles was compared to the of an IVIVC for metoprolol tartrate
experimental data points using tablets using two formulations.
prediction error metrics. Previously, we have internally validated
Figure 5, 6 and 7 illustrate the a correlation using a total of three
observed and IVIVC model metoprolol formulations designed to release the
plasma concentrations for each drug at a slow, moderate and fast rate.4
formulation using the S/M, M/F and S/F
IVIVC models, respectively.
An average percent prediction error for
Cmax and AUC of less than 10% was
The validity of the correlations was found for the IVIVC model developed
assessed by determining how well the with all three formulations.
IVIVC models could predict the rate
and extent of metoprolol absorption as
The average percent prediction error of
characterized by Cmax and AUC. less than 10% indicates that the three-
formulation correlation was predictive
Table 2 presents the percent errors and allows the associated dissolution
estimated for the difference between data to be used as a surrogate for
the observed and predicted Cmax and bioavailability studies.
AUC values for the S/M, M/F and S/F
IVIVC models.
Our current analysis examined how
well two formulations were able to
Table 2. Regression Parameters for IVIVC Models of Metoprolol accurately predict
IVIVC Models the in vivo
Formula Types Slope Intercept r P value bioavailability
S/M 1.171 -0.191 0.991 p <0.001 profile of various
M/F 1.207 -0.276 0.966 p <0.001 extended release
S/F 1.131 -0.203 0.946 p <0.001 formulations of
metoprolol.

None of the model predicted IVIVC models developed with

parameters deviated from the combinations of the slow and
experimental values by more than moderate, moderate and fast and slow
twelve percent (12%). and fast formulations were able to
DISCUSSION accurately predict the rate of metoprolol
absorption from the extended release
The availability of a meaningful IVIVC formulations.
of high quality and predictability for an
extended release formulation should Prediction errors for Cmax were all less
provide a sound foundation for product than 6%, except for the slow and
optimization. moderate IVIVC that displayed an error

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 International Journal of Generic Drugs

of 11.38 % (Table #3). AUC prediction References & Literature Cited

1. Guidance for the Industry: Extended Release
errors were all less than 10% Solid Oral Dosage Forms: Development, Evaluation
irrespective of the formulations used to and Application of In Vitro/In vivo Correlations. U.S.
develop the IVIVC suggesting that the Department of Health, Food and Drug
Administration, Center for Drug Evaluation and
IVIVC models also predicted the extent Research (CDER), July 1997.
of drug absorption. 2. Rekhi GS, Eddington ND, Fossler MJ and
Augsburger LL. Evaluation of In Vitro Release Rate
According to the IVIVC guidance, the and In Vivo Absorption characteristics of Four
average prediction error across Metoprolol Tartrate Immediate Release Tablet
formulations cannot be greater than Formulations. Pharml Dev Tech. 29(1), 11-24, 1997.
3. Eddington ND, Ashraf M, Leslie JL, Fossler MJ
10% and a formulation cannot have a and Augsburger LL. Identification of Formulation
prediction error greater than 15%. and Manufacturing Variables that Influence In Vitro
Dissolution and In Vivo Bioavailability of Propranolol
Based on these criteria, each of the Hydrochloride Tablets. Pharmaceutical Dev Tech. 3,
IVIVC models is valid in terms of the 535-547, 1998.
rate and extent of drug absorption. 4. Eddington ND, Marroum P, Uppoor R, Hussain
A and Augsburger L. Development and Internal
In summary, correlations were Validation of an In Vitro In Vivo Correlation for
Hydrophilic Metoprolol Tartrate Extended Release
developed with combinations of two Tablet Formulations. Pharm. Res. 15, 466-473,1998
formulations (e.g. slow and moderate, 5. Amidon, G. L., H. Lennernas, V. P. Shah, and
moderate and fast, slow and fast). J. R. Crison, “A Theoretical Basis For a
Biopharmaceutic Drug Classification: The
The evaluation of the correlation of Correlation of In Vitro Drug Product Dissolution and
FRD vs. FRA displayed a significant In Vivo Bioavailability,” Pharmaceutical Research,
linear relationship for each of the 12: 413-420, 1995.
6. Mistry B, Leslie J and Eddington, ND.A
combinations. Sensitive Assay of Metorpolol and its Major
As observed with correlation Metabolite α-hydroxy Metoprolol in Human Plasma
developed with three formulations, and Determination of Dextromethorphan and its
Metabolite Dextrophan in Urine with High
each correlation here was able to Performance Liquid Chromatography and
accurately estimate the rate as well as Flurometric Detection J Pharmaceut Biomed Anal.,
the extent of absorption. These results 16, 1041 –1049, 1998.
7. J.W. Moore and H.H. Flanner. Pharm Tech. 6:
indicate that a predictive correlation 64-74 (1996).
can be developed with two or three 8. Modified Release Solid Oral Dosage Form
formulations with this Class I agent and Guidance: Scale-up and Postapproval Changes:
Chemistry, Manufacturing and Controls, In Vitro
this suggests that similar results may Dissolution Testing and In Vivo Bioequivalence
be observed with other agents in this Documentation. U.S. Department of Health, Food
and Drug Administration, Center for Drug Evaluation
classification. Table 3.
and Research (CDER), September, 26, 1997
Cmax and AUC Prediction Errors (%) for Metoprolol Editorial correspondence and reprint requests to:
IVIVC Natalie D. Eddington, Ph.D. Pharmacokinetics
Biopharmaceutics Laboratory Department of
Cmax Pharmaceutical Sciences School of Pharmacy,
Formulation S/M M/F S/F University of Maryland at Baltimore 100 Penn
Street, AHB Baltimore, MD 21201-6808 (410) 706-
Slow -11.38 -3.75 -3.75 6710 (410) 706-6580 (fax)
Moderate -1.55 5.18 4.25
EIGHT IVIVC STUDIES in 2000
Fast -1.83 3.55 5.74 This article represents the first in the
series of eight IVIVC reviews by the author
AUC in a joint collaboration project with the
Formulation S/M M/F S/F International Drug Development
Slow -5.77 1.05 1.05 Association – IAGIM Full details of the 12
month joint venture with the University of
Moderate 1.52 7.07 6.94
Maryland VA USA and IAGIM can be
Fast -0.97 3.71 6.25 viewed at: http://www.locum.co.il/future

http://www.locumusa.com International Journal 422 of Generic Drugs e-* [email protected]

ISSN 0793 694X - US/Canada ISSN 0793 7784 Euro ISSN 0793 7822 - Pacific Rim
 International Journal 423 of Generic Drugs

Figure 1.
Mean dissolution and absorption profiles for the SLOW and MODERATE Formulation:
(A) Fraction of drug dissolved (FRD) and (B) Fraction of drug absorbed (FRA).

1.2 1.2

1.0 1.0

0.8 0.8
FRD

FRA
0.6 0.6

Moderate
0.4 0.4
Slow

0.2 0.2

0.0 0.0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Time (hrs) Time (hrs)

(A) (B)
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Figure 2. Mean dissolution and absorption profiles for the MODERATE and FAST Formulation:
(A) Fraction of drug dissolved (FRD) and (B) Fraction of drug absorbed (FRA).

1.2 1.2

1.0 1.0

0.8 0.8

FRA
FRD

0.6 0.6

0.4 0.4
Moderate
Fast
0.2 0.2

0.0 0.0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Time (hrs) Time (hrs)

(A) (B)
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 International Journal 425 of Generic Drugs

Figure 3.
Mean dissolution and absorption profiles for the SLOW and FAST formulation:
(A) Fraction of drug dissolved (FRD) and (B) Fraction of drug absorbed (FRA).

1.2 1.2

1.0 1.0

0.8 0.8
FRD

FRA
0.6 0.6

0.4 0.4
Fast
Slow
0.2 0.2

0.0 0.0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Time (hrs) Time (hrs)

(A) (B)

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 International Journal 426 of Generic Drugs

Figure 4.
IVIVC model linear regression plots of FRA vs FRD:
(A) SLOW and MODERATE Formulations, (B) MODERATE and FAST Formulations and (C) SLOW and FAST Formulations.

1.2 1.2 1.2

0.9 0.9 0.9

FRA

FRA

FRA
0.6 0.6 0.6

0.3 0.3 0.3

0.0 0.0 0.0

0.0 0.3 0.6 0.9 1.2 0.0 0.3 0.6 0.9 1.2 0.0 0.3 0.6 0.9 1.2
FRD FRD FRD

(A) (B) (C)

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 International Journal 427 of Generic Drugs

Figure 5.
Observed and predicted metoprolol plasma concentration for the SLOW and MODERATE IVIVC:
(A) SLOW Formulation, (B) MODERATE Formulation and (C) FAST Formulation.

80 100 120

100
80
60
Metoprolol (ng/ml)

Metoprolol (ng/ml)

Metoprolol (ng/ml)
80
60
40 60
40
40
20
20
20

0 0 0
0 5 10 15 20 25 0 5 10 15 20 25 0 5 10 15 20 25
Time (hr) Time (hr) Time (hr)

(A) (B) (C)

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 International Journal 428 of Generic Drugs

Figure 6.
Observed and predicted metoprolol plasma concentration for the MODERATE and FAST IVIVC:
(A) SLOW Formulation, (B) MODERATE Formulation and (C) FAST Formulation.

80 100 120

100
80
60
Metoprolol (ng/ml)

Metoprolol (ng/ml)

Metoprolol (ng/ml)
80
60
40 60
40
40
20
20
20

0 0 0
0 5 10 15 20 25 0 5 10 15 20 25 0 5 10 15 20 25
Time (hr) Time (hr) Time (hr)

(A) (B) (C)

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 International Journal 429 of Generic Drugs

Figure 7.
Observed and predicted metoprolol plasma concentration for the SLOW and FAST IVIVC:
(A) SLOW Formulation, (B) MODERATE Formulation and (C) FAST Formulation.

80 100 120

100
80
60
Metoprolol (ng/ml)

Metoprolol (ng/ml)

Metoprolol (ng/ml)
80
60
40 60
40
40
20
20
20

0 0 0
0 5 10 15 20 25 0 5 10 15 20 25 0 5 10 15 20 25
Time (hr) Time (hr) Time (hr)

(A) (B) (C)

International Journal 429 of Generic Drugs