DRUG
`
`FORMULATION
`
`
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 1
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`

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`DRUG
`
`BY
`
`I. RACZ, C. Sc. (Chem.)
`Professor of Pharmaceutical Technology
`and Pharmacokinelics
`
`Semmelweis University Medical School
`Budapest, Hungary
`
`FORMULATION
`
`
`
`
`t
`
`'
`
`.
`
`
`
`JOHN WILEY AND SONS, CHICHESTER ' NEW YORK '
`BRISBANE ' TORONTO ' SINGAPORE 1989
`
`
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`
`
`This is a revise
`
`
`
`
`d version 01' the Hungarian Gyégyszeiformula'la’s published by Medicina Kényvkiadé,
`‘ Budapest 1984
`
`© I. Récz 1989
`
`K1] rights reserved. No part of this book may be reproduced by any means, or transmitted, or translated
`into machine language without the written permission of the publisher.
`
`
`
`Récz, I. (Istvén)
`Drug formulation.
`
`Joint edition with Akadémiai Kiadé, Budapest
`
`Library of Congress Cataloging in Publication Du ta:
`
`
`
`Bibliography: p.
`Includes index.
`1. Chemistry, Pharmaceutical. 2. Pharmacokinetics.
`I. Title.
`[DNLMz l. Biopharmaceutics. 2. Chemistry,
`Pharmaceutical QV 744 R123]
`RS403.R23 1987
`615’.19
`ISBN 0 471 90517 8
`
`87-10520
`
`
`
`British Library Cataloguing in Publication Data:
`
`Récz, 1‘.
`Drug formulation.
`1. Chemistry, Pharmaceutical
`I. Title
`615’. 19
`
`R5403
`
`ISBN 0 471 90517 8
`
`Printed in Hungary
`
`--—.—.mr~
`
`]
`
`
`
`H
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 3
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`

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`solve the emerging problems in a successful and reproducible manner.
`The experiments within individual phases (zero to four) described in Table 1.1. do
`not necessarily proceed in exact sequence. Results from one experiment may determine
`the extent of parallel examinations. So, for example, if pharmacologic screening of
`an active ingredient during the zero phase did not show any biologic activity, no
`pre—formulation experiments would be performed unless the former result could be
`changed (e.g. by the addition of a substance which increased absorption). Phar—
`maceutical formulation experiments in phases zero to three are indispensable.
`However, these experiments must not be regarded as simple, routine tasks since the
`development of marketable products is highly dependent on the expert’s scientific
`knowledge and creativity during these experimental phases. The complete de-
`velopment ofa drug to the marketing stage may take ten to twelve years [2] depending
`primarily on the resourcefulness of the manufacturer and on the legal rules of the
`given country.
`
`1.1. PRE-FORMULATION STUDIES
`
` pharmacologists, physicians, mathematicians, economists, etc.) who work together to
`
`Pre-forrnulation studies in pharmacy are sometimes defined as those that precede
`product development. The investigator should critically consider the physical-chem—
`ical data even prior to animal testing to provide the development pharmacist with
`some key facts. These facts will bear upon such things as (a) preparing drug samples
`for animal tests in a way that optimizes chances for the compound to exert its
`pharmacological action,
`{b) ways to solubilize the compound, (c) determining
`photosensitivity or other aspects of its chemical stability, etc. These studies commonly
`take a month or two to perform.
`.
`Pre-formulation studies [18] in a-broader sense, and applied to a broader spectrum
`‘special chemical products, may be defined as those preceding the actual establish-
`. 1ent of the final formula and working directions for product manufacture. These
`4 ay take years to carry out. In this book emphasis is on formulation ofdrug products,
`mt pre—formulation is addressed in broad sense. It discusses the approach to
`"ormulation work in pre-development, development, pilot scale-up studies, and
`pre-manufacturing development. It tries to show what studies are required and how
`to perform them in order to get uniformly good drug products of high quality [16].
`When a potentially marketable new active ingredient is identified, it is important
`to find the most satisfactory and efficacious pharmaceutical dosage form. Such
`preparations must be stable, compatible, bioavailable and able to be manufactured
`in an economical manner. Pro—formulation experiments are designed to answer these
`basic questions on a small scale [21].
`The most important is that the active ingredient possess appropriate biological
`activity or at least be a chemical analogue which has advantageous actions or
`therapeutic properties when compared with the parent compound. When favourable
`rncnlh: have harm moor-ted from the pharmacological and acute toxicity tests, the
`
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`Exhibit 2013 Page 4
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 4
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`

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`Table 1.1. Outline for the development of a new active ingredient into a pharmaceutical product
`PHASE 0
`0.1. Conception, synthesis, synthesis of radio-labelled compound.
`0.2. Physicochemical investigations.
`0.3. Preliminary analytical studies on the active ingredient.
`0.4. Screening for biological activity.
`‘
`0.5. Acute and subchronic toxicity tests.
`0.6. Pre-formulation experiments.
`0.7. Marketing prognosis.
`
`PHASE I.
`1.1. Clinical phase 1. Examination of tolerance in healthy human volunteers.
`Selection of a suitable pharmaceutical dosage form and strength Determined from preliminary
`short—term ADME tests and estimated pharmacokinetic parameters.
`1.2 Investigation of metabolic pathways of the drug.
`1.3. Chronic toxicity tests.
`1.4. Investigation of mutagenic, teratogenic and carcinogenic effects.
`1.5. Investigation of the active ingredient—DNA repair system.
`1.6. Synthetic chemical experiments concerning scale up and manufacture of the experimental industrial
`product.
`1.7. Drug formulation experiments (stability, compatibility, biopharmaoeutics, dosage regimen design, etc).
`1.8. Total analytical investigation of the active ingredient, elaboration of stability testing methods and
`assays for specific measurements of metabolitets).
`1.9. Elaboration of marketing plans.
`
`PHASE 2.
`2.1. Clinical phase II. Randomized double blind, controlled clinical trials to verify the pharmacological
`effect in the patient population indicated. Long-term ADME tests and estimation of pharmacokinetic
`parameters.
`2.2. Drug formulation experiments. Determination ofbioavailability. Elaboration ofproduction guidelines.
`Pharmaceutical pilot plant experimental work. Scale up experiments. Middle scale production of
`clinical samples.
`2.3. Analytical investigation of pharmaceutical product.
`2.4. Administrative work in accordance with marketing plans.
`2.5. Marketing.
`
`PHASE 3.
`3.1. Wide-spreading clinical trials. Evaluations of the side-effects and possible drug interactions.
`32. Large-scale manufacturing of the pharmaceutical products. Determination of the shelf-life.
`3.3. Elaboration of quality norms for the product.
`3.4. "Administrative work in accordance with marketing plans. Registration certificate.
`3.5. Detailed marketing for estimation of claims and requirements.
`
`PHASE 4. (Summarizing, evaluation)
`4.1. Data concerning the synthesis.
`4.2. Analytical data.
`4.3. Manufacturing data.
`4.4. Clinical data (field of indication, directions for use).
`4.5. Registration.
`4.6. Marketing data.
`4.7. Production data.
`4.8. Patent situation.
`
`r—._._._._.—_......+—.
`
`
`“hm—us_____.—..—_._.
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 5
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`
`
`At this time, information obtained during chemical synthesis (i.e., possible de-
`composition products, deteriorating by—products, etc.) along with preliminary analyt-
`ical data are at the disposal of the pre-formulation scientists.
`Schematically, the process of pre—formulation experiments may be summarized as
`follows. The list is by no means complete since separate formulas must be developed
`for special cases, and of course, the physical state (solid, liquid) of the active ingredient
`must be considered. Nevertheless, the scheme presents a logical sequence of experi—
`ments presently used in pre-forrnulation development of a pharmaceutical product.
`It is important to emphasize that the scheme contains the elaboration of production
`formulas and working directions as well as standards of quality. In fact, these are
`described in the formulation section, however, they are presented here to show the
`unity of the whole process.
`
`1.1.]. CONV ENTIONAL PHARMACEUTICAL
`PREPARATIONS
`
`1.1.1.1. HDMDGENEOUS LIQUID-PHASE PHARMACEUTICAL
`PREPARATIONS
`
`Characteristics of the active ingredient
`1.
`1.1. Colour, odour, taste, consistency.
`1.2.
`Solubility.
`1.2.1. Solubility in hydrophilic solvents (ethanol, isopropanol, 1,2-propylene glycol,
`glycerol, polyethylene glycol 300, acetone, etc).
`1.2.2. Dependence of solubility on pH in buffered aqueous systems (pH range 3—7).
`1.2.3. Solubility in lipophilic solvents (chloroform, propellents (fluorinated hydrocar~
`bons) methylene chloride, vegetable oils, isopropyl myristate, etc). These data
`are needed for planning biopharmaceutical experiments (i.e., absorption, distri-
`bution, excretion).
`1.2.4. Solubility in artificial gastric and intestinal juices at 37°C.
`1.3. Melting point.
`1.4. Data on analytical purity.
`1.4.1. Loss during exposure to dry or humid conditions.
`1.4.2. Ignition residue.
`1.4.3. Inorganic elements and heavy metals.
`1.4.4. Organic impurities.
`1.4.5. Differential scanning calorimetry characteristics.
`1.5.
`pH and/or pK values of the active ingredient.
`1.6. Qualitative analytical data.
`' 1.6.1. Identification reactions.
`1.6.2. IR- and UV-spectra.
`1.6.3. Identity and purity assay by thin layer chromatography.
`1.7. Quantitative analytical data.
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 6
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 6
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`
`
`1.7.2.
`1.7.3.
`1.8.
`
`2.1.
`2.2.
`2.3.
`2.4.
`2.5.
`2.6.
`2.7.
`2.8.
`
`3.1.
`3.2.
`3.3.
`3.4.
`
`Analytical methods to detect specific decomposition products.
`Analytical methods applicable to pharmacokinetic measurements.
`Preliminary stability data (effects due to exposure to light, various pHs and
`solvents, and oxygen). Usually a 0.1—0.5 per cent aqueous solution-of the active
`ingredient buffered to pH values between 2 and 8 are stored at room temperature
`and at 50°C. If the solubility of the active ingredient is limited, small quantities
`of a semi—polar solvent are added to improve the solubility. The quantity of
`active ingredient in the samples is periodically determined using analytical
`methods sensitive for the detection of specific decomposition products. These
`stability experiments last for 1-4 weeks. depending on the chemical structure
`of the active ingredient.
`
`Characteristics of the pharmaceutical product
`Colour, odour, taste, consistency.
`pH value.
`Density.
`Viscosity.
`Surface tension.
`Refraction index.
`Solid material content.
`
`Isotonia (if necessary).
`
`Compatibility testing of the pharmaceutical product
`Drug—drug interactions.
`Drug—excipient interactions.
`Excipient—excipient interactions.
`Interactions of the drug and/or excipients with the packaging materials.
`
`4.1.
`4.1.1.
`4.1.2.
`4.2.
`4.2.1 .
`
`4.2.2.
`
`4.3.
`
`4.4.
`
`Stability testing of the pharmaceutical product
`Physical stability.
`Cold endurance (storage at 5°C for an extended time period).
`Possibility of dilution.
`Qualitative chemical stability.
`Light stability. Stability against UV-irradiation. The sample is moved in a
`planar field (16 rotations per minute) for 5 h at a distance of 50 cm from a
`750 W mercury-vapor lamp. Changes in composition are determined.
`Heat stability. (It is advisable to proceed with the experiments until a significant
`change in stability is observed.) Heat stabiiity is determined on samples stored
`at 40, 50 and 60°C for 30 days. In the case of sterile preparations, stability at
`120°C for 20 min is also determined. Chemical changes in the heat-treated
`samples are determined to measure stability.
`Quantitative chemical stability. The expiration date is determined using stan-
`dardized, predictive kinetic methods and measuring specific decomposition
`products.
`Microbiological stability. Sporostatic, fungistatic, and bacteriostatic activity is
`determined in a cultured media with different concentrations of the pharmaceuti-
`nnl «rntIIInf I: n
`1-H:ot\f:r\fia mm (iv-nub nnlnrinnn fr“- "nun-”J n1nnvln“'!r- n+n\
`
`“HAM
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 7
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 7
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`4.5.
`
`4.6.
`
`4.7.
`
`5.1.
`5.1.1.
`5.1.2.
`5.1.3.
`5.2.
`5.2.1.
`
`6.
`61
`6.1.1.
`6.1.2.
`6.2.
`
`6.3.
`6.4.
`6.4.1.
`6.4.2.
`6.4.3.
`
`6.4.4.
`6.5.
`6.6.
`
`Toxicological stability. The toxicity of the product must not change sigr
`ficantly after long-term storage or heat treatment.
`Therapeutic stability. The therapeutic effect of the product must not chan;
`significantly after long-term storage or heat treatment.
`Stabilization experiments.
`
`Formula and working directions for the production of the drug
`Composition data.
`Actual composition of the pharmaceutical product.
`Description, qualitative characteristics, and information about excipients adde
`Directions for weighing.
`Technological operations.
`List of necessary operations for production (i.e., requirements for dissolutic
`sequence of steps in formulation, time required for production. manpower 31
`system requirements, aseptic techniques, sterilization procedures, etc.).
`
`Biopharmaceutical and pharmacokinetic data
`Characterization of dissolution rates.
`Intrinsic dissolution rate of the drug.
`Changes in dissolution rate in the presence of surfactants.
`Distribution coefficients. Possible lipophilic solvents include: n-hexane, octanr
`and chloroform. The pH value of the aqueous solution should be 1.2 and 6
`respectively, at 37”C.
`Modelling of absorption in vitro.
`Pharmacokinetic data.
`.
`Determination of the elimination rate constant. .
`Determination of the half-life of the actiVe ingredient in viva.
`Determination of steady-state serum concentrations after repeated administl
`tion.
`Determination of bioavailability (if not administered intravenously).
`Elaboration of the dosage regimen and directions for use.
`Drug metabolism data.
`
`Directions for storage and packaging
`
`Health and accident prevention provisions
`
`1.1.1.2. HETEROGENEOUS SOLID-PHASE PHARMACEUTICAL PRODUCTS
`
`1.1.
`1.2.
`1.3.
`
`1.4.
`1.5.
`1.6.
`
`Physical characteristics of the active ingredient
`Crystal structure. Salt form, if a salt.
`Particle size and its distribution and/or specific surface area.
`Weight volume (the volume of 100 g of substance). Volume weight (the weig
`of 100 cm3 of substance).
`Density.
`Colour, odour, taste, consistency.
`Flowability.
`
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 8
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`

`li-
`
`In,
`1d
`
`ht
`
`.._.—______....._._.——-——-
`
`-—__'i...—'-__..;..__..-_____..._____....._
`
`2.1.
`2.1.1.
`
`2.1.2.
`
`2.1.3.
`
`2.1.4.
`2.2.
`2.3.
`2.4.
`2.5.
`
`Physicochemical characteristics of the active ingredient
`Solubility.
`Solubility in hydrophilic solvents (ethanol, isopropanol, 1,2-propylene glycol,
`glycerol, polyethylene glycol 300, acetone, etc.).
`Solubility in lipophilic solvents (chloroform, propellants (fluorinated hydrocar-
`bons) methylene chloride, vegetable oiis, isopropyl myristatc, etc.).
`Dependence of solubility on pH (usually in the range of 3—7) in buffered aqueous
`systems.
`Solubility in artificial gastric and intestinal juices at 37°C.
`Melting point.
`pK of the active ingredient.
`Equilibrium vapor pressure, hygroscopicity.
`Wettability (Enslin number).
`
`3.1.
`3.2.
`3.3.
`
`4.1.
`
`4.2.
`
`4.3.
`
`4.4.
`
`5.
`5.1.
`
`5.2.
`5.2.1.
`
`Analytical data on the active ingredient
`Analytical purity data (see l.1.1.1.~l.4.).
`Qualitative analytical data (see 1.1.1.1.—l.6.).
`Quantitative analytical data (see l.1.l.1.—1.7.).
`
`Compatibility examinations
`Physical and chemical compatibility. The active substance is mixed (1: 1) with
`carriers and excipients that may be used in the formulation. These mixtures
`are adjusted to 5 per cent humidity conditions and kept in closed vessels in an
`air thermostat at 50°C for 10 days. Data before and after the treatment are
`evaluated.
`_
`Determination of the optimal pH. The dissolved or dry active substance is
`examined in-different buffered solutions (pH 2—7) or 5 g powder mixtures are
`moistened with approximately 3 per cent solutions. These are kept in an air
`thermostat in closed vessels at 50°C for 10 days. Data before and after treatment
`are evaluated to select the most desirable buffer additive, if needed.
`Optimal humidity is determined according to the stability test results obtained
`from studies of samples at various humidity conditions.
`Comment: Samples after tests 4.1., 4.2., and 4.3. must undergo semivquantitative
`thin layer chromatography for examination of possible decomposition products.
`Chemical structures of the decomposition products should be determined, if
`possible, in order to understand the stoichiometry of decomposition pathways.
`Interactions of the active ingredients and excipients with packaging materials.
`
`Stability testing
`Physical stability. Stability of the crystal structure is tested by examining
`morphological changes caused by pressure (30 t/cmz), heat, drying and moisture.
`Qualitative chemical stability.
`Light stabiiity. Against natural light: stability is determined by measuring the
`chemical changes which a sample undergoes when irradiated for 10 days by a
`150 W xenon lamp at a distance of 40 cm. The temperature should 'not exceed
`15°C. Against UV—light (see 1.l.1.l.—4.2.1.).
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 9
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 9
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`

`

`
`
`5.2.2.
`
`5.2.3.
`5.3.
`5.4.
`
`5.5.
`5.6.
`5.7.
`
`Thermal stability. It is advisable to test at least 3 dispersions of dilferent humidity
`by storing them at 40, 50 and 60°C'for a period of 30 days.
`‘
`Determination of susceptibility to oxidation.
`Quantitative chemical stability (determination of expiration date).
`Microbiological stability. Bacteria count determination of a fresh sample of the
`active ingredients and a sample kept open in the laboratory for one week. The
`bacteria count of granules or the final product indicates impurities introduced
`with excipients during operation steps. The bacteria count after one week of
`exposure indicates the potential for microorganism proliferation.
`Toxicological stability (see l.1.l.1.—4.5.).
`Therapeutical stability (see l.1.1.1.—4.6.).
`Stabilization experiments.
`
`6.1.
`6.1.1.
`6.1.2.
`6.1.3.
`6.1.4.
`6.2.
`6.2.1.
`
`6.2.2.
`6.3.
`6.3.1.
`
`6.3.2.
`
`Directions and guidelines for drug production
`Composition data.
`Actual composition.
`Description. qualitative characteristics and information about the excipients.
`Instructions for weighing.
`Directions concerning compatible and non-compatible excipients.
`Technological operations.
`List of necessary operations (e.g., direct tabletting, wet or dry granulating, order,
`time, energy requirements of operational steps, etc).
`Diagram and interval of drying.
`,
`Parameters achievable by the technological operations.
`Granulates (powder mixtures): weight volume, distribution of particle size,
`flowability, optimal humidity, equilibrium vapor pressure, and compatibility.
`Tablets, dragees, capsules, dragee cores: geometrical data, weight, solidity.
`disintegration time, resistance to abrasion and humidity.
`Biopharmaceutical and pharmacokinetic data of the pharmaceutical product
`Characterization of the dissolution rate.
`Intrinsic dissolution rate of the drug.
`Apparent dissolution rate of the drug in the dosage form.
`Changes of the dissolution rate in the presence of surfactants.
`Distribution coefficient (see 1.1.1.1.—6.2.).
`In vitro absorption modelling.
`Pharmacokinetic data.
`Determination of the absorption rate constant.
`Determination of the elimination rate constant.
`Calculation of the biologic half-life of the drug.
`Pharmacokinetic evaluation following single dose, multiple dose and chroni
`administration. Determination of steady-state concentrations.
`Determination of bioavailability.
`Metabolism data.
`
`7.1.
`7.1.1.
`7.1.2.
`7.1.3.
`7.2.
`7.3.
`7.4.
`7.4.1.
`7.4.2.
`7.4.3.
`7.4.4.
`
`7.4.5.
`7.5.
`
`Directions for storage and packaging
`Health and accident prevention provisions
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 10
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`UCB Biopharma SPRL (IPR2019-00400)
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`

`

`1.1.1.3. HETEROGENEOUS FLUID- AND SEMI-SOLED-PHASE PHARMACEUTICAL PRODUCTS
`
`1.
`
`Physical characteristics of the active substance (The appropriate tests must
`be carried out for solid or liquid active ingredients, respectively.)
`1.1. Crystal structure. Isomorphism, polymorphy.
`1.2.
`Particle size and particle size distribution.
`1.3. Weight volume (the volume of 100 g substance). Volume weight (the weight of
`100 cm3 substance).
`1.4. Density:
`1.5. Colour, odour, taste, consistency.
`1.6. Viscosity.
`
`2.
`2.1.
`
`Physicochemical characteristics of the drug
`Solubility (see 1.1.1.2.—2.1.—-2.1.3.). It is necessary to extend the tests to include
`excipients which may be used in formulation (i.e., carriers in suppositories,
`ointments, etc.).
`2.2. Melting point.
`2.3. Wettability (Enslin number).
`2.4.
`pK of the active ingredient.
`
`Analytical data about the active ingredient
`3.
`3.1. Analytical purity data (see 1.1.1.1.—l.4.).
`3.2. Qualitative analytical data (see 1.1.1.1.—1.6.).
`3.3. Quantitative analytical data (see l.1.1.1.—1.7.).
`
`4.
`
`Compatibility testing. During control testing. in addition to the normal tests,
`it is also advisable to examine the range of the particle size distribution,
`rheological parameters, melting point, setting point, dropping point, separation
`of components, sedimentation, and redispersability.
`4.1. Examination of drug—drug interactions.
`4.2. Examination of drug—excipient interactions.
`4.3. Examination of interactions among excipients.
`
`5.
`
`Stability testing. It is desirable to carry out stability testing with samples of
`optimum composition.
`Physical stability.
`5.].
`5.1.1. Cold endurance and freeze-thaw stability.
`5.1.2. Determination of the maximal temperature which does not cause changes in
`consistency.
`5.2. Qualitative chemical stability.
`5.2.1. Light stability (see 1.1.1.2.—5.2.1.).
`5.2.2. Heat stability determined on the basis of physical properties of the drug product
`(tn-n).
`5.2.3. Examination of susceptibility to oxidation.
`5.3. Quantitative chemical stability. The expiration date of the active ingredient is
`determined on the basis of principles of reaction kinetics with the measurement
`of specific decomposition products.
`
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`Exhibit 2013 Page 11
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`UCB Biopharma SPRL (IPR2019-00400)
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`

`

`5.4. Microbiological stability. Testing of sporostatic, fungistatic, and bacteriostatic
`activities of appropriately contaminated drug products.
`5.5. Toxicological stability (see 1.1.1.1.—4.5.).
`5.6. Therapeutical stability (see 1.1.1.1.—4.6.).
`5.7.
`Stabilization experiments.
`
`Formula and working directions for the production of the drug
`6.
`6.]. Composition data.
`6.1.1. Actual compasition of the pharmaceutical product.
`6.1.2. Description, qualitative characteristics, and information about excipients.
`6.1.3. Dosage instructions (disclosure of the extruding factor in case of suppositories).
`6.1.4. Instructions concerning compatible and non—compatible excipients.
`6.2. Technological operations.
`6.2.1. List of necessary operations for production.
`6.2.2. Type, intensity, and duration of mixing.
`6.2.3. Parameters of heat treatment.
`6.2.4. Cooling parameters.
`6.3.
`Parameters achievable by the technological operations (related to the type of
`drug product): particle size, particle size distribution, setting point, flowing point,
`flowing curves, dropping point, thixotropy, sedimentation rate, cream forming,
`separation, redispersability, breaking hardness, melting time, dissolution time.
`
`Biopharmaceutical data on the drug product
`7.
`7.1. Characterization of dissolution rate.
`7.1.1. Intrinsic dissolution rate of the drug.
`7.1.2. Apparent dissolution rate of the drug from the dosage form.
`7.1.3. Changes in dissolution rate in the presence of surfactants.
`7.2. Distribution coefficients (see 1.1.1.1.—6.2.).
`7.3. Modelling of absorption in vitro.
`7.4.
`Pharmacokinetic data
`7.4.1. Determination of the absorption rate constant.
`7.4.2. Determination of the elimination rate constant.
`7.4.3. Calculation of the biological half-life of the drug.
`7.4.4. Pharmaeokinetic evaluation following single dose, multiple dose and chronic
`administration. Determination of steady-state concentrations.
`7.4.5. Determination of bioavailability.
`7.5. Metabolism data.
`
`8.
`
`9.
`
`Directions for storage and packaging
`
`Health and accident prevention provisions
`
`1.1.1.4. OTHER PHARMACEUTICAL PRODUCTS
`
`According to statistical data, the drug types listed above represent 90 to 95 per
`cent of all conventional dosage formulations. In the case of less common drug forms
`which were not discussed. e.g., the aerosols, additional pro-formulation aspects must
`
`
`
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`UCB Biopharma SPRL (IPR2019-00400)
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`also be considered (e.g., solubility and dissolution rate of the drug in the propellent,
`determination of film elasticity, its drying time, the equilibrium gas tension in the
`case of aerosols for wound dressing, etc).
`
`1.1.2. NON-CONVENTIONAL LONG-ACTING
`PHARMACEUTICAL PRODUCTS
`
`Since the 19305 pharmaceutical industry has spent most of its research efforts on
`the synthesis of new molecules. Consequently, the development and application of
`new methods or modes of administration of pharmaceutical compounds have
`progressed very slowly. The present methods of therapy using conventional drugs,
`which form the majority of pharmaceuticals, are rather quantitative {with solid phase
`forms) or concentrational (with liquid phase forms). The very long-acting dosage
`formulations developed in the last decade summarize and,
`in addition to the
`above-mentioned aspects, also use the knowledge of such time-dependent factors as
`the absorption and elimination rates, and the duration of treatment.
`Major advantages of very long—acting dosage forms include the less frequent
`administration of the dosage form along with increased bioavailability, and a decrease
`in side-effects.
`In some ways,
`the process of pro-formulation and formulation
`examination of long-acting pharmaceutical dosage forms differs from those described
`above. The following pre-formulation scheme depicts the differencies in the rational
`evaluation of both types of dosage forms.
`
`Pharmacokinetic examinations
`1.
`1.1. Compilation of pharmacological, toxicological and clinical experimental data
`for the active ingredient or the drug product and evaluation of its suitability
`as a very long-acting drug product.
`Preliminary pharmacokinetic experiments.
`1.2.
`in the organism.
`1.2.1. Qualitative testing of the fate of the active ingredient
`Identification of the metabolites and determination of the primary routes of
`elimination.
`1.2.2. Elaboration of specific quantitative microanalytical methods for determination
`of the active ingredient and its metabolites in the biological fluids and tissues.
`1.2.3. Examination of the interaction between the drug and serum proteins.
`1.2.4. Elaboration and choice of methods for determination of therapeutic activity.
`1.2.5. Construction of a pharmacokinetic model.
`1.3.
`Pharmaéokinetic experiments.
`1.3.1. Construction of time—action curves upon a single intravenous and single
`and repeated oral administration of the active ingredient with the following
`variables:
`
`drug concentration in blood
`drug concentration in urine
`metabolite(s) concentration in blood
`metabolite(s) concentration in urine
`drug concentration in faeces
`bound drug concentration
`
`vs time
`vs time
`vs time
`vs time
`vs time
`vs time
`
`
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`UCB Biopharma SPRL (IPR2019-00400)
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`1.3.2. Quantitative relationship of pharmacological activity with the pharmacokinetic
`profile of the drug
`1.4. Evaluation of pharmacokinetic experiments.
`1.4.1. Analysis and modelling of the pharmacokinetic data using an analogue or
`digital computer.
`1.4.2. Examination and correlation of the drug activity and the pharmacokinetic
`parameters.
`
`1.4.3. Calculation of minimum and maximum values for blood or other biological
`tissue levels needed to assure therapeutic activity.
`1.4.4. Calculation of dose and pharmacokinetie parameters for a sustained release
`formulation.
`'
`
`Biopharmaceutica] examinations
`2.
`2.1. Determination of the dissolution rate of the drug and its derivatives (free acid
`or base, salts, esters, and possible prodrugs) in vitro as a function of pH and
`enzyme content of the solvent.
`
`2.2.
`2.3.
`
`In vitro absorption rate experiments and its relationship to pH.
`Selective optimization of methods for reducing the dissolution rate of a given
`drug with regard to production possibilities.
`2.4. Biopharmaoeutical characterization of pharmaceutical dosage form (dissolution
`rate, absorption rate, etc.).
`
`Instructions and proposals for drug production
`3.
`3.]. Data concerning drug product composition.
`3.1.1. The actual composition.
`3.1.2. Description and qualitative characteristics of new excipients.
`3.1.3. Directives concerning compatible and non—compatible excipients.
`3.1.4. Instructions for weighing.
`3.2. Technological operations. Complete description of proposed operations.
`3.3. Characterization of parameters achievable by the technological operations.
`4.
`Pharmaceutical stability and compatibility data (see 1.1.1.)
`5.
`Pharmacokinetic data
`5.1. Experiments in animals with usual and with very long-acting drug formulations
`in order to compare toxicities.
`5.2. Comparative phannacokinetic experiments in humans to determine the absorp—
`tion and activity of the very long-acting dosage form.
`5.3. Determination of the bioavailability of the drug in this dosage form.
`5.3.1. Data on the relative onset of action.
`5.3.2. Data on the relative duration of action.
`
`6.
`7.
`
`Directions for storage and packaging of the drug formulation
`Health and accident prevention provisions
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`UCB Biopharma SPRL (IPR2019-00400)
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`1.2. DRUG FORMULATION
`
`Numerous steps are involved in developing a therapeutically active compound into
`a marketable drug product. Initial preform ulation experiments are designed to study
`the physical and chemical properties of the compound with the intent of selecting a
`dosage formulation of optimum composition. Carefully detailed, small-scale pre-
`formulation studies are performed before a dosage formulation is developed and
`subjected to pilot and finally large-scale industrial production. Once a dosage
`formulation is approved for use in the market place, production on a large-scale will
`be required. This will necessitate the use of large volumes of raw material, automation
`in the production and packaging of the dosage formulation, and the development of
`quality control standards to assure the stability, uniformity, purity, and identity of
`the drug product.
`
`1.3. MATHEMATICAL DESIGN
`OF PRE-FORMULATION
`AND FORMULATION EXPERIMENTS
`
`Initial formulation experiments should be designed to generate pertinent data
`regarding physical and chemical properties of the drug and to identify appropriate
`excipients which could be used in the formulation. The formulator must also consider
`the quality and aesthetic nature of the final product, as well as the economic feasibility
`of large-scale production. These experiments must be carefully designed to collect
`this information in a timely manner. The primary purpose of this chapter is to present
`a general overview of how pre—formulation experiments are designed. It would be
`impossible to present a detailed discussion of experimental design within this chapter.
`
`1.3.]. ESTABLISHING THE LEVEL OF SIGNIFICANCE
`
`Pre-formulation studies should be designed to provide objective experimental
`results. For example, controversial data may be found in the literature regarding the
`inhibition of drug absorption by various excipients in tablet and suppository
`formulations. However, much of the controversy is based on subjective opinions
`rather than objective experimental results. It is evident that whenever data are analysed
`in an experiment, a level of statistical significance must be established in order to
`correctly and logically interpret the data.
`Subjective evaluation of data may be sufficient if the results are significantly different
`from results expected due to random fluctuations. When evaluating results, the
`investigator should apply uniform criteria. However, if large differences in the data
`occur due to random fluctuations, intuitive judgement may be misleading. In this case,
`experiments should be designed and statistically evaluated for significance.
`In
`industrial experiments ideal circumstances cannot always be achieved. Therefore, the
`results may not a