HANDBOOK OF
`Pharmaceutical
`Manufacturing
`Formulations
`
`Sterile Products
`
`__ ——
`
`VOLUME 6
`Sarfaraz K. Niazi
`
`CRC PRESS
`
`Boca Raton London New York
`
`Washington, D.C.
`
`EXHIBIT
`
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`

`

`Library of Congress Cataloging-in-Publication Data
`
`Niazi, Sarfaraz, 1949
`Handbook of pharmaceutical manufacturing formulations / Sarfaraz K. Niazi.
`p. cm.
`Includes bibliographical references and index.
`Contents: — v.6. Sterile products.
`ISBN 0-8493-1751-7 (alk. paper)
`1. Drugs — Dosage forms — Handbooks, manuals, etc. I. Title
`
`RS2OO.N53 2004
`615T9-dc21
`
`2003051451
`
`This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and
`sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information,
`but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use.
`
`Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including
`photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from
`the publisher.
`
`The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale.
`Specific permission must be obtained in writing from CRC Press LLC for such copying.
`
`Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431.
`
`Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and
`explanation, without intent to infringe.
`
`Visit the CRC Press Web site at www.crcpress.com
`
`© 2004 by CRC Press LLC
`
`No claim to original U.S. Government works
`International Standard Book Number 0-8493-1751-7
`Library of Congress Card Number 2003051451
`Printed in the United States of America 1 234567890
`Printed on acid-free paper
`
`UNIVERSITY LIBRARY
`
`-------- _
`
`linn
`
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`

`Dedication
`
`To Professor Shamsuz Zoha, my first pharmacy teacher, who inspired many
`with his passion for the profession and for science
`
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`

`

`Preface to the Series
`
`No industry in the world is more highly regulated than
`the pharmaceutical industry because of potential threat to
`a patient's life from the use of pharmaceutical products.
`The cost of taking a new chemical entity (amortized over
`the cost of all molecules racing) to final regulatory
`approval is a staggering $800 million, making the phar­
`maceutical industry one of the most research-intensive
`industries in the world. In the year 2004. it is anticipated
`that the industry will spend about $20 billion on research
`and development. The generic market of drugs as the new
`entities come off patent is one of the fastest growing
`segments of the pharmaceutical industry, with every major
`multinational company having a significant presence in
`this field.
`Whereas many stages of new drug development are
`inherently constrained with time, the formulation of drugs
`into desirable dosage forms remains an area where expe­
`diency can be practiced with appropriate knowledge by
`those who have mastered the skills of pharmaceutical for­
`mulations. The Handbook of Pharmaceutical Manufactur­
`ing Formulations is the first major attempt to consolidate
`the available knowledge about formulations in a compre­
`hensive, and by nature a rather voluminous, presentation.
`The book is divided into six volumes, based strictly
`on the type of formulation science involved in the devel­
`opment of these dosage forms: sterile products, com­
`pressed solids, uncompressed solids, liquid products,
`semisolid products, and OTC products. The separation of
`OTC products even though they may easily fall into one
`of the other five categories is made to comply with the
`industry norms of separate research divisions for OTC
`products. Sterile products require skills related to steril­
`ization of product, and of less importance is the bioavail­
`ability issue, which is an inherent problem of compressed
`
`dosage forms. These types of considerations have led to
`the classification of products into these six categories.
`Each volume includes a description of regulatory fil­
`ing techniques for the formulations described. Also
`included are the current regulatory guidelines on cGMP
`compliance specific to the dosage form. Advice is offered
`on how to scale up the production batches.
`It is expected that formulation scientists will use this
`information to benchmark their internal development pro­
`tocols and cut the race to file short by adopting formulae
`that have survived the test of time. Many of us who have
`worked in the pharmaceutical industry suffer from a close
`paradigm when it comes to selecting formulations — “not
`invented here" perhaps reigns in the mind of many sea­
`soned formulations scientists subconsciously when they
`prefer to choose only a certain platform for development.
`It is expected that with the quick review of possibilities
`available to formulate made available in this book, scien­
`tists will benefit from the experience of others.
`For the teachers of formulation sciences, this series
`offers a wealth of information. Whether it is a selection
`of a preservative system or the choice of a disintegrant,
`the series offers a wide choice to study and rationalize.
`Many have assisted me in the development of this
`work that has taken years to compile, and I thank scores
`of my graduate students and colleagues for their help. A
`work of this size cannot be produced without errors,
`although I hope that these errors do not distract the reader
`from the utility of the book. 1 would sincerely appreciate
`if readers point out these mistakes for corrections in future
`editions.
`
`Sarfaraz K. Niazi, Ph.D.
`Deerfield, Illinois
`
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`

`Preface to the Volume
`
`The Handbook of Pharmaceutical Manufacturing Formu­
`lations: Sterile Products (HPMF/SP) is written for the
`pharmaceutical scientist and others involved in the regu­
`latory filing and manufacturing of new sterile products.
`No other area of regulatory compliance receives more
`attention and scrutiny by regulatory authorities than the
`regulation of sterile products, for obvious reasons. With
`the increasing number of potent products, particularly the
`new line of small protein products, joining the long list
`of proven sterile products — mainly parenteral and oph­
`thalmic products — the technology of manufacturing ster­
`ile products has evolved into a very sophisticated industry.
`The entry barrier to this technology is much higher com­
`pared with those for other dosage forms. Consequently,
`the cost of production remains high as well. In recent
`years, regulatory agencies around the world have taken
`very serious notice of the deficiencies in the manufactur­
`ing specifications of the active raw material intended for
`parenteral administration. New guidelines for the API and
`aseptic processing of sterile products are the main issues
`of concern today for manufacturers. This volume of
`HPMF/SP does not delve into details related to starting
`material issues. Of interest in this issue are formulations
`of sterile dosage forms, regulatory filing requirements of
`sterile preparations, and cGMP compliance, all of which
`are tied together in the final preparation of the Chemistry,
`Manufacturing, and Control (CMC) sections of regulatory
`applications.
`Chapter 1 describes the specifications of a manufac­
`turing facility to manufacture compliant sterile products.
`Chapter 2 outlines the New Drug Application (NDA) or
`ANDA (Abbreviated New Drug Application) filing
`requirements of sterile products. Chapter 3 describes in
`detail the layout of formulations provided in the book.
`This chapter must be thoroughly examined to make the
`best use of this book. Because the intent of the information
`provided in this book is to help the formulator develop a
`product for regulatory filing, boilerplate details are left
`out. Chapter 3 provides these details and also makes strong
`recommendations on how the formulator can benefit from
`the information available from suppliers of components
`and chemicals used in the formulation.
`These three chapters are followed by the body of the
`book, which provides an alphabetical presentation of for­
`mulations of pharmaceutical products based on their
`generic names. There are three types of formulation
`entries. In the first type, both the bill of materials and
`
`manufacturing directions are provided. This type is further
`composed of two types, wherein greater detail is provided
`for some products. This differentiation is intentional
`because the common details are often omitted in subse­
`quent presentations. The second type of formulations is
`provided with bill of materials only. This may include
`products for which the manufacturing directions are obvi­
`ous to a prospective manufacturer, particularly in light of
`the details already provided for similar products elsewhere
`in the book, and also those products for which such infor­
`mation is not readily available. The third category of for­
`mulations includes experimental formulations, which may
`not yet have been commercialized or received regulatory
`approvals. These formulations are included to show to the
`formulation scientist unique opportunities that exist for
`the chemical entity in question.
`Formulations of biotechnology-derived drugs are
`provided with some additional details and remain
`restricted to declaration of composition, yet they provide
`a good overview of the complexities involved in such
`formulations.
`In consolidating the details of formulations, efforts
`have been made to present them in as unified a form as
`possible; nevertheless, some nonuniformities exist
`because of the large variety of presentations possible for
`the wide diversity of formulations presented in the book.
`A limited number of products intended for veterinary use
`are also included. These products are subject to cGMP
`compliance similar to that for human products.
`The formulations provided here meet the 4S
`requirements:
`
`• Safety. This is an important issue for parenteral
`products; the choice of excipients is limited by
`this consideration. In most of the formulations,
`the ingredients are fully approved by the regu­
`latory authorities; in some formulations, the
`active drug moiety may have been banned in
`some countries, for example, dipyrone.
`• Sterility. The compositions presented are fully
`sterilizable either by terminal treatment or by
`aseptic processing; where preservatives are
`added, these are in sufficient quantity to fulfill
`the dedicated function.
`• Stability. Besides the rigor of treatment in ren­
`dering a product sterile, incompatibility issues
`may render a sterile product prone to instability.
`
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`

`The formulations included here have been fully
`validated to provide sufficient shelf-life,
`depending on the product.
`• Scalability. Whereas the batch formulation is
`presented for a 1-1 batch, these formulations are
`linearly scalable. Manufacturing losses have
`been included and these formulations can be
`readily scaled up to any size; of course, the
`requirements of size change in the validation
`protocol should be considered.
`
`One of the best utilities of the database included in this
`book is to benchmark the products intended for develop­
`ment. A large number of formulation possibilities exist
`for any drug; though with the 4S limitations, the choice
`of ingredients (excipients) narrows rather rapidly. Multi­
`vitamin formulations are one such example wherein
`extreme instability and cost considerations have resulted
`in a variety of formulations. A study of many possibilities
`tells us about the problems we can anticipate while for­
`mulating these products. In some instances, only compo­
`sition details are provided, along with raw material man­
`ufacturing details, because they are often an integral part
`of the formulation, such as in the case of biotechnology-
`derived products. Whereas this information may be at best
`cursory, it is useful to provide a study of these product
`formulations.
`The information contained in this book has been
`obtained mainly from sources open to the public. It has
`taken years to accumulate this database and no warranties
`are provided that these formulation compositions will not
`infringe on any proprietary product or intellectual prop­
`erty. The formulators must consider this before using the
`information. Also, as with all scientific experimental data,
`it should be understood that replication is subject to many
`factors, including type of equipment used, grade of mate­
`rial employed, and other processing techniques imple­
`mented. The road to converting these formulations to
`
`validated parts of a CMC package for submission to reg­
`ulatory authorities is a long one; nevertheless, working
`with these formulations will reduce the risk of prolonged
`experimentation, and for generic formulation develop­
`ment, it will expedite entrance to the market. Some sci­
`entists may find this information useful in improving their
`products for any of the 4S considerations. More informa­
`tion is available on the website of Pharmaceutical Scien­
`tist, Inc. (http://www.pharmsci.com), wherein scientists
`can find updated information on regulatory compliance
`and additional tools for writing the CMC portions of the
`ANDA and NDA filings. The readers are encouraged to
`consult this website.
`Although I have tried to sift through the large data­
`bases in both the formative and proofreading stages of the
`handbook, it is possible that errors remain. I would appre­
`ciate it if readers point these out to me by e-mailing me
`at niazi@pharmsci.com.
`I am grateful to CRC Press for taking this lead in
`publishing what is possibly the largest such work in the
`field of pharmaceutical sciences. It has been a distinct
`privilege to know Mr. Stephen Zollo, senior editor at CRC
`Press. Stephen has done more than what any editor can
`do to encourage an author into conceiving, planning, draft­
`ing, and finally, despite many reasons why it could not be
`done, completing the work on a timely basis. I am greatly
`indebted to him. The editorial assistance provided by CRC
`Press staff was indeed exemplary, particularly the help
`given by Erika Dery, Gail Renard, Sara Kreisman. and
`others at CRC Press. Although the editors and proofread­
`ers have pored over this book diligently, any mistakes
`remaining are altogether mine.
`
`Sarfaraz K. Niazi, Ph.D.
`Pharmaceutical Scientist, Inc.
`20 Riverside Drive
`Deerfield, Illinois 60015
`
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`About the Author
`
`Dr. Sarfaraz K. Niazi has been teaching and conducting research in the pharma­
`ceutical industry for over 30 years. He has authored hundreds of scientific papers,
`textbooks, and presentations on the topics of pharmaceutical formulation, biophar­
`maceutics, and pharmacokinetics of drugs. He is also an inventor with scores of
`patents and is licensed to practice law before the U.S. Patent and Trademark Office.
`Having formulated hundreds of products from consumer products to complex bio­
`technology-derived products, he has accumulated a wealth of knowledge in the
`science of formulations and regulatory filings of Investigational New Drugs (INDs)
`and New Drug Applications (NDAs). Dr. Niazi advises the pharmaceutical industry
`internationally on issues related to formulations, pharmacokinetics and bioequivalence
`evaluation, and intellectual property issues (http://www.pharmsci.com).
`
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`106
`
`Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products
`
`B-Complex Vitamin Veterinary
`
`Bill of Materials (Batch Size 1 L)
`Item
`Material
`Scale/mL
`Pyridoxine HCI, USP. as Riboflavin-5'-Phosphate Sodium
`1
`10.00 mg
`2
`d-Panthenol
`15.00 mg
`Cyanocobalamin USP
`3
`150.00 Pg
`Choline Chloride
`4
`10.00 mg
`Cobalt Gluconate
`5
`0.70 mg
`Copper Gluconate
`6
`0.20 mg
`Ferric Ammonium Citrate
`7
`15.00 mg
`Benzyl Alcohol, NF
`8
`2.00 %
`Niacinamide, USP
`9
`100.00 mg
`Chlorobutanol Anhydrous, USP
`10
`5.00 mg
`Inositol
`11
`10.00 mg
`12
`Biotin
`10.00 pg
`Methionine. NF
`13
`20.00 mg
`J/-Lysine
`14
`20.00 mg
`Glycine
`20.00 mg
`15
`Water for Injection. USP, QS to
`QS mL
`16
`
`Bill of Materials (Batch Size 1 L)
`Material
`Item
`Scale/mL
`Thiamine HCI, USP
`1
`150.00 mg
`Niacinamide, USP
`2
`150.00 mg
`Riboflavin as Riboflavin-5'-Phosphate Sodium
`3
`2.00 mg
`J-Panthenol
`4
`10.00 mg
`Pyridoxine HCI, USP
`5
`10.00 mg
`Choline Chloride
`20.00 mg
`6
`Inositol
`20.00 mg
`7
`Cyanocobalamin, USP
`100.00 pg
`8
`Benzyl Alcohol. NF
`2.00 %
`9
`Water for Injection, USP, QS to
`10
`QS mL
`
`Bill of Materials (Batch Size 1 L)
`Item
`Material
`Scale/mL
`1
`Niacinamide, USP
`125.000 mg
`Ascorbic Acid as Sodium Ascorbate, USP
`100.000 mg
`2
`Riboflavin-5'-Phosphate Sodium
`5.000 mg
`3
`4
`5.000 mg
`Pyridoxine HCI, USP
`50.000 mg
`</-Panthenol
`5
`Methyl Paraben. USP
`1.169 mg
`6
`7
`0.134 mg
`Propyl Paraben. USP
`QS mL
`Water for Injection. QS to
`8
`Hydrochloric Acid for pH adjustment
`QS mL
`9
`
`Quantity UOM
`10.00
`g
`15.00
`g
`150.00 mg
`10.00
`g
`0.70 g
`0.20
`g
`15.00 g
`2.00 %
`100.00
`g
`5.00
`g
`10.00 g
`10.00 mg
`20.00
`g
`20.00 g
`20.00
`g
`1.00 L
`
`Quantity UOM
`150.00 g
`150.00
`g
`2.00
`g
`10.00
`g
`10.00
`g
`20.00
`g
`20.00
`g
`100.00 mg
`2.00 %
`1.00 L
`
`Quantity UOM
`125.000 g
`100.000 g
`5.000 g
`5.000 g
`50.000 g
`1.169
`g
`0.134
`g
`1.00 L
`QS mL
`
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`

`Sterile Pharmaceutical Formulations
`
`107
`
`Bill of Materials (Batch Size 1 L)
`Scale/mt
`Item
`Material
`1
`100.00 mg
`Choline Chloride
`2
`50.00 mg
`Inositol
`3
`50.00 mg
`Methionine, NF
`4
`2.00 %
`Benzyl Alcohol, NF
`5
`QS mL
`Water for Injection. QS to
`QS mL
`6
`Hydrochloric Acid for pH adjustment
`
`B-Complex with Minerals Injection (Veterinary)
`
`Bill of Materials (Batch Size 1 L)
`Scale/mL
`Item
`Material
`1
`10.00 mg
`Thiamine HO, USP
`Pyridoxine HO, USP
`2
`1.00 mg
`3
`Riboflavin-5'-Phosphate Sodium
`1.50 mg
`d-Panthenol
`4
`7.00 mg
`Cyanocobalamin, USP
`50.00 Wg
`5
`Sodium Chloride, USP
`6
`8.00 Pg
`Copper Gluconate
`7
`0.10 mg
`Cobalt Gluconate
`1.00 mg
`8
`Ferric Ammonium Citrate (16% to 18% elemental iron)
`9
`8.00 mg
`Niacinamide, USP
`100.00 mg
`10
`11
`Benzyl Alcohol, NF
`1.50 %
`Water for Injection, USP, QS to
`12
`QS mL
`
`B-Complex Vitamins with Hormones
`
`Bill of Materials (Batch Size 1 L)
`Item
`Scale/mL
`Material
`Testosterone, NF
`10.00 mg
`1
`Estrone, NF
`2
`0.50 mg
`Cyanocobalamin, USP
`3
`100.00 Pg
`Thiamine HC1, USP
`4
`50.00 mg
`Pyridoxine HC1, USP
`5
`1.00 mg
`6
`5.00 mg
`rf-Panthenol
`Niacinamide, USP
`7
`100.00 mg
`Lidocaine HCI, USP
`20.00 mg
`8
`Carboxymethylcellulose Sodium. USP
`0.20 %
`9
`Sodium Phosphate. USP
`10
`0.20 %
`Benzyl Alcohol, NF
`4.00 %
`11
`Water for Injection, USP. QS to
`12
`QS mL
`
`Quantity UOM
`100.00
`g
`50.00
`g
`50.00
`g
`2.00 %
`1.00 L
`QS mL
`
`Quantity UOM
`10.00 g
`1.00
`g
`1.50
`g
`7.00
`g
`50.00 mg
`8.00 mg
`0.10 g
`1.00
`g
`8.00
`g
`100.00
`g
`1.50 %
`1.00 L
`
`Quantity UOM
`10.00 g
`0.50
`g
`100.00 mg
`50.00
`g
`1.00
`g
`5.00 g
`100.00 g
`20.00
`g
`0.20 %
`0.20 %
`4.00 %
`L
`1.00
`
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`

`150
`
`Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products
`
`Cyanocobalamin, Pyridoxine, and Thiamine Injection
`
`Bill of Materials (Batch Size 1 L)
`Material
`Scale/mL
`Item
`1
`Thiamine HCI, 20% excess’
`33.33 mg
`2
`Pyridoxine HCI, 20% excess6
`33.33 mg
`0.33 mg
`3
`Cyanocobalamin Crystalline/ 40% excess
`4
`Benzyl Alcohol
`10.00 mg
`5
`Sodium Hydroxide*1
`QS mg
`6
`Hydrochloric Acid, 1 N
`QS mL
`7
`Water for Injection. QS to
`QS mL
`8
`Nitrogen Gas
`QS —
`(100)
`(ioo)
`a Quantity of thiamine HC1 = 40 x ...... - — - x--------------------------- g
`100-% moisture % Assay on dry basis
`(ioo)
`(too)
`b Quantity of pyridoxine HCI = 40 x---------------------- x-------------------------- g
`100 - % moisture % Assay on dry basis
`
`(100) (100)
`1 Quantity of cyanocobalamin = 0.47 x---------------------- x—
`-------------------- g
`100-% moisture % Assay on dry basis
`d For pH adjustment, make 10% sodium hydroxide solution.
`
`Quantity DOM
`40.00
`g
`40.00
`g
`0.47
`g
`10.00
`g
`QS mg
`QS mL
`1.00 L
`QS —
`
`MANUFACTURING DIRECTIONS
`
`1. Check Item 7 to be used for solution preparation
`and verify that it meets conductivity (NMT 1.0
`pS/cm) and pH (5.0 to 7.0).
`2. Put 900 mL of Item 7 into the preparation vessel
`and bubble N, gas to expel dissolved oxygen
`(O2% Limit =*NMT 1).
`3. Add and dissolve Item 4 into Step 2 preparation
`vessel. Mix well with stirring to make clear
`solution. Then, dissolve Items 1 and 2 and make
`clear solution.
`4. Put 9 mL of Item 7 into flask, slowly add Item
`3, and make slurry of Item 3.
`5. Transfer Item 3 slurry from Step 4 to the solu­
`tion, rinse the flask two or three times with Item
`7, and transfer to the above solution. Mix well
`till it becomes clear solution.
`6. Check pH (range 3.5 to 4.0). Adjust pH if nec­
`essary with 10% NaOH solution or 1 N HO
`solution.
`7. After adjustment of the pH, make up volume to
`1 L by adding Item 7 and mix while bubbling
`
`N2 gas until O2% is less than 1. Check final pH
`(range 3.5 to 4.0). Sample.
`8. Clean and sterilize filtration assembly before
`starting the primary filtration. Check the integ­
`rity of filter cartridge by the bubble point test.
`9. Transfer the solution from the preparation ves­
`sel to mobile vessel through filtration assembly
`containing 0.45-pm filter cartridge.
`10. Sterilize the ampoules by dry heat.
`11. Before starting the final filtration, check the
`integrity of filter cartridge by the bubble point
`test.
`12. Aseptically connect the N2 line through sterile
`N, filter to the inlet of mobile vessel. Check the
`validity of N2 filter.
`13. Aseptically connect one end of previously ster­
`ilized filtration assembly with 0.22-pm pore­
`size filtration cartridge to the outlet of mobile
`vessel and other end to buffer holding tank on
`the ampoules filling machine parts. Filter the
`solution.
`14. Fill solution from the bulk into each sterile dry
`clean ampoule and seal it. Perform the leak test.
`
`Apotex (IPR2019-00400) Ex. 1037 p. 010
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`

`Sterile Pharmaceutical Formulations
`
`151
`
`Bill of Materials (Batch Size 1 L)
`Material
`Item
`Scale/mL
`1
`100.00 mg
`Thiamine HC1. USP
`100.00 mg
`Pyridoxine HC1. USP
`2
`Cyanocobalamin, USP
`3
`1000.00
`Benzyl Alcohol, NF
`15.00 mg
`4
`QS mb
`5
`Water for Injection, USP. QS to
`os mb
`Sodium Hydroxide for pH adjustment
`6
`
`Quantity UOM
`100.00
`g
`100.00
`g
`1000.00 mg
`15.00 mg
`1.00 L
`QS
`
`MANUFACTURING DIRECTIONS
`
`1. Vitamin formulations are highly prone to deg­
`radation and are affected by exposure to light
`and air. As a general rule, these must be man­
`ufactured protecting them from light and pro­
`viding continuous N2 (or in some cases CO2)
`cover.
`2. Use freshly distilled and freshly autoclaved
`(121°C for 30 min) Item 10; bubble Item 11 for
`20 min.
`3. Add and dissolve Items 4 and 5 to Item 10 at
`70°C; allow to cool.
`
`4. Add Items 6, 7, and 8 and stir to dissolve.
`5. Add 1, 2. 3 to step 4, one at a time, and with
`complete solution stirring.
`6. Check pH to 3.8 to 4.0; adjust pH with Item 12
`or 13.
`7. Filter aseptically through a 0.45-pm prefilter
`and a 0.22-pm membrane filter into a staging
`sterilized vessel.
`8. Fill into sterilized (200°C for 4 h) amber Type
`1 glass ampoule using pre- and post-item 11
`flushing.
`9. Sample for complete testing.
`
`Apotex (IPR2019-00400) Ex. 1037 p. 011
`
`

`

`160
`
`Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products
`
`4: Dexamethasone Sodium Phosphate Injection
`
`Bill of Materials (Batch Size 1 L)
`Scale/mL
`Item
`Material
`Dexamethasone Phosphate, use Dexamethasone Sodium
`4.00 mg
`1
`Phosphate, USP
`Creatinine
`Sodium Citrate, USP, Dihydrate Powder
`Sodium Metabisulfite. NF
`Methyl Paraben. NF (Aseptoform M) Powder
`Propyl Paraben. NF (Aseptoform P) Powder
`Sodium Hydroxide”
`Water for Injection, USP. QS to
`Nitrogen Gas, NF
`
`8.00 mg
`10.00 mg
`1.00 mg
`1.50 mg
`0.20 mg
`QS mg
`QS mt
`QS
`
`2
`3
`4
`5
`6
`7
`8
`9
`
`Quantity UOM
`a
`4.40
`
`8.00
`g
`10.00
`g
`1.00
`g
`1.50
`g
`0.20
`g
`QS mg
`1.00 L
`QS —
`
`" Use for pH adjustment only.
`
`MANUFACTURING DIRECTIONS
`
`1. Preparation of solution. Note: Use N, protec­
`tion throughout process.
`a. Heat 80% of final volume of Item 8 to boil­
`ing.
`b. Dissolve Items 5 and 6 in Step a with N2
`flushing.
`c. Discontinue heating and allow solution to
`cool to room temperature slowly while bub­
`bling N2 through solution.
`d. Add and dissolve Items 1, 2. 4, and 3 in
`Step c with continuous N, flushing.
`e. Check pH (range 7.0 to 8.5). Adjust pH to
`8.0 if necessary, using freshly prepared 10%
`sodium hydroxide solution. Sample.
`f. QS to final volume with N,-saturated
`Item 8.
`
`5: Dexamethasone Injection. Veterinary
`
`Bill of Materials (Batch Size 1 L)
`Scale/mL
`Material
`Item
`2.00 mg
`1
`Dexamethasone, USP
`Methyl Paraben, USP
`1.80 mg
`2
`0.20 mg
`Propyl Paraben, USP
`3
`0.18 mg
`Benzyl Alcohol. NF
`4
`0.05 mL
`Ethyl Alcohol, USP
`5
`50.00 %
`Polyethylene Glycol 400, USP
`6
`QS mL
`Water for Injection, QS to
`7
`
`g. Filter solution through a previously rinsed
`filtration setup, using a 0.45-pm or finer
`membrane and a prefilter.
`•h. Prepare for the filling line a sterile 0.22-pm
`membrane filtration setup.
`2. Preparation of ampoules. Use Type I I -mL
`glass ampoules. Wash and dry ampoules and
`sterilize by using dry heat at 200°C (-0, +50°C)
`glass temperature, for 225 min (-0, +360 min).
`This or cycle providing equivalent heat input
`may be used.
`3. Filling. Note: Careful protection with N, is
`essential for stability.
`a. Aseptically connect tank and sterile filter
`setup.
`b. Fill specified amount into each clean, dry,
`sterile ampoule. Sample.
`c. Flush with sterile-filtered N2 and seal.
`Sample.
`
`Quantity UOM
`2.00
`g
`1.80
`g
`0.20
`g
`0.18
`g
`0.05
`g
`50.00 %
`1.00 L
`
`Apotex (IPR2019-00400) Ex. 1037 p. 012
`
`

`

`Sterile Pharmaceutical Formulations
`
`161
`
`6: Dexamethasone Sodium Phosphate Injection
`
`Bill of Materials (Batch Size 1 L)
`Scale/mL
`Item
`Material
`1
`4.00 mg
`Dexamethasone, as Dexamethasone Sodium Phosphate
`2
`8.00 mg
`Creatinine
`3
`10.00 mg
`Sodium Metabisulfite
`Disodium Edetate
`4
`1.00 mg
`10.00 mg
`5
`Sodium Citrate
`Methyl Paraben Sodium
`0.18 %
`6
`7
`0.02 %
`Propyl Paraben Sodium
`8
`Propylene Glycol
`0.02 mL
`QS mL
`9
`Water for Injection, USP. QS to
`10
`0.030
`Sodium Hydroxide. NF. for pH adjustment
`g
`Nitrogen Gas, NF
`11
`QS
`
`Quantity UOM
`5.20
`g
`8.00 g
`10.00
`g
`1.00
`g
`10.00
`g
`oe>
`1.80
`0.20 g
`20.00 mL
`1.00 L
`3.00
`g
`QS
`
`MANUFACTURING DIRECTIONS
`
`1. Autoclave Item 9 at 121 °C for 30 min and use
`this throughout manufacture.
`2. Heat 0.2 L of Item 9 to 80°C and dissolve Items
`5 and 7 in it.
`3. In a separate vessel, dissolve Item 5 in 0.1 L of
`Item 9
`4. In a separate vessel, dissolve Items 3 and 4 in
`0.1 L of Item 9.
`5. Add contents of Steps 2 and 3 into Step 1, mix
`thoroughly, and then add Item 8 with mixing.
`6. Add and dissolve Item 10 in 0.4 L of Item 9
`and add to Step 5.
`7. Make up the volume to 0.99 L.
`8. Filter the solution in Step 6, using a presteril­
`ized assembly and a 0.45-pm prefilter and a
`0.22-pm filter into a sterile vessel.
`
`9. Autoclave solution in Step 7 at 121 °C for 20
`min.
`10. On cooling to room temperature, add Items I
`and 2 to Step 8 and mix.
`11. Check pH and adjust to between 7.5 and 8.5
`with 4 N presterilized sodium hydroxide
`solution.
`12. Make up the volume to 1.0 1 with Item 9.
`13. Filter through presterilized assembly, using a
`0.45-(j.m prefilter and a 0.22-pm filter into a
`staging sterilized vessel.
`14. Fill 2.1 mL into presterilized Type I flint vials
`with pre- and postflush with Item 11. Use neo­
`prene rubber stoppers sterilized by autoclaving
`at 121 °C for 20 min.
`15. Fill under aseptic conditions.
`
`Apotex (IPR2019-00400) Ex. 1037 p. 013
`
`

`

`200
`
`Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products
`
`Etorphine Hydrochloride Veterinary
`
`Bill of Materials (Batch Size 1 L)
`Material
`Item
`Scale/ml
`Etoiphine Hydrochloride (M-99)
`1
`1.00 mg
`Sodium Hydroxide, USP
`2
`3.40 mg
`Disodium Edetate
`0.50 mg
`3
`Citric Acid, USP
`4
`14.00 mg
`Propylene Glycol. USP
`5
`0.50 mg
`Benzyl Alcohol. NF
`6
`5.00 mg
`Water for Injection, USP, QS to
`QS mL
`7
`
`Exemestane Aqueous Suspension Injection
`
`Bill of Materials (Batch Size 1 L)
`Material
`Item
`Scale/mL
`Exemestane (micronized)
`1
`100.00 mg
`Methyl Paraben
`1.80 mg
`2
`Propyl Paraben
`3
`0.20 mg
`Sodium Chloride
`4
`8.30 mg
`Polyethylene Glycol 400
`5
`30.00 mg
`Polysorbate 80 (Tween®)
`2.00 mg
`6
`Methylcellulose
`7
`1.50 mg
`Lecithin
`8
`5.00 mg
`L-Methionine
`9
`1.00 mg
`Edetate Sodium
`10
`0.50 mg
`Sodium Phosphate Monobasic Hydrate
`11
`0.694 mg
`Sodium Phosphate Dibasic Dodecahydrate
`0.588 mg
`12
`Sodium Hydroxide for pH adjustment
`QS mL
`13
`Hydrochloric Acid for pH adjustment
`14
`QS mL
`Water for Injection, USP, QS to
`QS mL
`15
`
`Quantity UOM
`1.00
`g
`3.40
`g
`0.50
`g
`14.00
`g
`0.50
`g
`5.00
`g
`1.00 L
`
`Quantity UOM
`100.00
`g
`1.80
`g
`0.20
`g
`CTO
`8.30
`CT©
`30.00
`2.00
`g
`1.50
`g
`5.00 g
`1.00
`g
`0.50
`g
`0.694
`g
`0.588
`g
`
`1.00 L
`
`MANUFACTURING DIRECTIONS
`
`1. Take 0.2 L of Item 15 in a suitable vessel and
`add and disperse Items 8 and 7 (adding in that
`order to the vessel); mix to obtain a homoge­
`nous dispersion.
`2. Autoclave at 121 °C for 15 min the preparation
`in Step 1.
`3. In another vessel, take 0.8 L of Item 15 and add
`and dissolve all other ingredients except Item 1.
`
`4. Pass the solution in Step 3 through a 0.22-pm
`filter to sterilize.
`5. Add preparation in Step 4 to preparation in
`Step 2 under aseptic conditions.
`6. Check and adjust pH to 6.0 to 7.0 with Item 13
`or 14.
`7. Add Item 1 (presterilized by heat) and homog­
`enize to form a smooth suspension.
`8. Fill.
`
`Apotex (IPR2019-00400) Ex. 1037 p. 014
`
`

`

`Sterile Pharmaceutical Formulations
`
`Flumazenil Injection
`
`Bill of Materials (Batch Size 1 L)
`Scale/mL
`Item
`Material
`1
`0.10 mg
`Flumazenil
`2
`1.80 mg
`Methyl Paraben
`0.20 mg
`3
`Propyl Paraben
`4
`9.00 mg
`Sodium Chloride
`5
`Disodium Edetate
`0.10 mg
`0.10 mg
`Acetic Acid. Glacial
`6
`7
`QS mb
`Sodium Hydroxide for pH adjustment
`QS mb
`8
`Hydrochloric Acid for pH adjustment
`Water for Injection, USP, QS to
`9
`QS mb
`
`Note: Adjust pH to 4.0 with Item 7 or 8.
`
`Folic Acid and Niacinamide Injection
`
`Bill of Materials (Batch Size 1 L)
`Material
`Item
`Scale/mL
`1
`Folic Acid, USP. 15% excess
`15.00 mg
`Niacinamide, USP. 15% excess
`150.00 mg
`2
`biquefied Phenol, NF
`0.5 %
`3
`Water for Injection, USP, QS to
`4
`QS mb
`Hydrochloric Acid for pH adjustment
`QS mb
`5
`Sodium Hydroxide for pH adjustment
`QS mb
`6
`Nitrogen Gas, NF
`7
`QS
`
`203
`
`Quantity UOM
`1.00 g
`1.80
`g
`0.20
`g
`9.00 g
`0.10 g
`0.10 g
`QS
`QS
`1.00 b
`
`Quantity UOM
`19.16
`g
`191.60
`g
`5.00
`g
`1.00 b
`QS
`QS
`QS
`
`MANUFACTURING DIRECTIONS
`
`1. Maintain cover of Item 7 throughout the man­
`ufacturing process.
`2. Dissolve Item 2 in 0.6 L of Item 4.
`3. Add Item 1 into Step 1 to make a suspension
`and dissolve it by slow addition of 40% of Item
`6 until dissolved; do not overadd Item 6.
`
`4. Dissolve Item 3 in 0.1 L of Item 4, and add this
`solution to that of Step 2 slowly.
`5. Make up volume; check and adjust pH to 6.8
`(6.5 to 7.0)
`6. Filter through a 0.45-pm prefilter and 0.22-pm
`filter into a presterilized staging assembly.
`7. Fill 10.5 mL into Type I 10-mL amber glass
`vials presterilized aseptically under cover of
`Item 7.
`
`Apotex (IPR2019-00400) Ex. 1037 p. 015
`
`

`

`Sterile Pharmaceutical Formulations
`
`207
`
`Gentamicin Injection
`
`20 mg/2 mL
`
`Bill of Materials (Batch Size 10 L)
`Item
`Material
`Scale/mL
`1
`10 mg
`Gentamicin Base. 3% excess (use equivalent amount of
`Gentamicin Sulfate), USP
`Methyl Paraben. USP
`Propyl Paraben. USP
`Sodium Edetate, USP
`Sulfuric Acid, Reagent-Grade Pellets, for pH adjustment
`Sodium Hydroxide Pellet for pH adjustment
`Water for Injection, USP
`Nitrogen Gas, NF
`
`1.2 mg
`0.2 mg
`0.11 mg
`QS
`QS
`QS mb
`QS
`
`2
`3
`4
`5
`6
`7
`8
`
`80 mg/2 mL
`
`Quantity UOM
`103.0
`g
`
`12.0
`g
`2.0 g
`0O
`1.1
`QS
`
`QS
`QS
`
`Quantity UOM
`412.00 g
`
`g
`g
`g
`
`18.00
`2.00
`1.10
`QS
`
`10.00 L
`QS
`
`Bill of Materials (Batch Size 10 L)
`Scale/mL
`Item
`Material
`1
`Gentamicin Base, 3% excess (use equivalent amount of
`40.00 mg
`Gentamicin Sulfate), USP
`Methyl Paraben, USP
`Propyl Paraben, USP
`Sodium Edetate, USP
`Sulfuric Acid, Reagent-Grade Pellets, for pH adjustment
`Sodium Hydroxide Pellets for pH adjustment
`Water for Injection, USP. QS to
`Nitrogen Gas, NF
`
`1.80 mg
`0.20 mg
`g
`0.11
`QS
`QS
`QS mb
`QS
`
`—m
`
`2
`3
`4
`5
`6
`7
`8
`
`Note: Quantity of gentamicin sulfate = (1000 x weight of gentamicin base)/(potency of gentamicin as base).
`
`MANUFACTURING DIRECTIONS
`
`1. Preparation of water.
`a. Check the water for injection used for solu­
`tion preparation and verify that it meets con­
`ductivity NMT 1.0 pS/cm.
`b. Take the sample for pH (range 5.0 to 7.0)
`2. Preparation of solution.
`a. Put 3.0 L of water for injection into the first
`20-L preparation vessel and bubble N, gas
`to expel dissolved O2 for 20 min.
`b. Put 9 L of water for injection (hot water,
`82°C to 85°C) in a second 20