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

`

` DRUG
`
`
`~ . FORMULATION
`
`
`{
`
`BY
`
`I. RACZ,C. Se. (Chem.)
`Professor of Pharmaceutical Technology
`and Pharmacokinetics
`
`/
`
`|
`
`Semmelweis University Medical School
`
`Budapest, Hungary
`
`JOHN WILEY AND SONS, CHICHESTER - NEW YORK:
`
`
`BRISBANE - TORONTO - SINGAPORE 1989
`
`
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 2
`
`

`

`
`
`
`This is a revised version of the Hungarian Gydégyszerformuldlds published by Medicina Konyvkiadd,
`- Budapest 1984
`
`
`
`All 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.
`
`© I. R&ez 1989
`
`Joint edition with Akadémiai Kiad6, Budapest
`
`Library of Congress Cataloging in Publication Data:
`
`Racz, I. (istvan)
`Drug formulation.
`
`
`
`
`Bibliography: p.
`Includes index.
`I. Chemistry, Pharmaccutical. 2. Pharmacokinetics.
`I. Title,
`[DNLM: I. Biopharmaceutics. 2. Chemistry,
`Pharmaceutical. QV 744 R123]
`RS403.R23 1987
`6157.19
`ISBN 0 471 90517 8
`
`87-10520
`
`British Library Cataloguing in Publication Data:
`
`Racz, I.
`Drug formulation.
`1. Chemistry, Pharmaceutical
`1. Title
`615°.19
`
`R5403
`
`ISBN 0 471 90517 8
`
`Printed in Hungary
`
`~_—neeM
`
`]
`
`
`
`4
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 3
`
`

`

`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 regardedas 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-
`velopmentofa drugto 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-formulation 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 exertits
`pharmacological action, (b) ways to solubilize the compound, (c) determining
`photosensitivity or other aspects ofits chemicalstability, etc. These studies commonly
`take a month or two to perform.
`Pre-formulation studies [18] in abroadersense, and applied to a broader spectrum
`“special chemical products, may be defined as those preceding the actual establish-
`ment of the final formula and working directions for product manufacture. These
`may take years to carry out. In this book emphasisis on formulation ofdrug products,
`but pre-formulation is addressed in broad sense. It discusses the approach to
`formulation 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. Pre-formulation experimentsare 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 of
`therapeutic properties when compared with the parent compound. When favourable
`vacnite have been revorted from the pharmacological and acute toxicity tests, the
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2013 Page 4
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 4
`
`

`

`Table 1.1. Outline for the development of a new active ingredientinto 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.
`
`PHASEI.
`1.1. Clinical phase I. Examination of tolerance in healthy human volunteers.
`Selection of a suitable pharmaceutical dosage form and strength. Determined from preliminary
`short-term ADMEtests 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 concerningscale up and manufacture of the experimental industrial
`product.
`1.7. Drug formulation experiments (stability, compatibility, biopharmaceutics, dosage regimen design, etc.).
`1.8. Total analytical investigation of the active ingredient, elaboration ofstability testing methods and
`assays for specific measurements of metabolite{s).
`1.9. Elaboration of marketing plans.
`
`PHASE 2.
`2.1. Clinical phase I. Randomized double blind, controlled clinical trials to verify the pharmacological
`effect in the patient population indicated. Long-term ADMEtests 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.
`
`PHASE3.
`3.1. Wide-spreadingclinical trials. Evaluations of the side-effects and possible drug interactions.
`3.2. 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)
`4.4. Data concerning the synthesis.
`4.2. Analytical data.
`43. Manufacturing data.
`4.4, Clinical data(field of indication, directions for use).
`4.5, Registration.
`4.6. Marketing data.
`4.7, Production data.
`48. Patent situation.
`
`aaaa
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2013 Page 5
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 5
`
`

`

`
`
`At this time, information obtained during chemical synthesis (1c. 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. Thelist is by no means complete since separate formulas must be developed
`for special cases, and of course, the physicalstate(solid, liquid) of the active ingredient
`must be considered. Nevertheless, the scheme presents a logical sequence of experi-
`ments presently used in pre-formulation development of a pharmaceutical product.
`It is important to emphasize that the schemecontains 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.
`
`1.1.1. CONVENTIONAL PHARMACEUTICAL
`PREPARATIONS
`
`LLLI. HOMOGENEOUS LIQUID-PHASE PHARMACEUTICAL
`PREPARATIONS
`
`Characteristics of the active ingredient
`1.
`1.1. Colour, odour, taste, consistency.
`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(Le., 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 valuesofthe 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.
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2013 Page 6
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 6
`
`

`

`
`
`1.7.2.
`1.7.3.
`1.8.
`
`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 aqueoussolution-ofthe 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 ingredientis 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
`methodssensitive 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—druginteractions.
`Drug-excipient interactions.
`Excipient—excipient interactions.
`Interactions of the drug and/or excipients with the packaging materials.
`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
`planarfield (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.
`. Heatstability. (It is advisable to proceed with the experiments until a significant
`changein stability is observed.) Heat stability 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 measurestability.
`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-
`nal wnendunt Gia
`iniantinne aa denne anhitinns fae eran d alanncine natn’
`
`4.1.1.
`4.1.2.
`4,2.
`4.2.1.
`
`4.3,
`
`44,
`
`ceee
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2013 Page 7
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 7
`
`

`

`4.5.
`
`4.6.
`
`4.7.
`
`5.1.
`Shligis
`5.1.2.
`5.1.3.
`
`5.2.1.
`
`6.
`6.1.
`6.1.1.
`6.1.2.
`6.2.
`
`6.3.
`
`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 a1
`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, octan:
`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 vivo.
`Determination of steady-state serum concentrations after repeated administ:
`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.
`1.2.
`1.3.
`
`1.4.
`
`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 cm? of substance).
`Density.
`Colour, odour, taste, consistency.
`Flowability.
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2013 Page 8
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 8
`
`

`

`SE
`
`liaEe
`
`mM,
`id
`
`ht
`
`Zils
`2.1.1.
`
`2.1.2.
`
`2.1.3.
`
`2.1.4.
`2.2.
`2.3.
`
`2.5,
`
`3.1.
`
`3.3.
`
`4.t,
`
`4.2,
`
`4.3.
`
`4.4,
`
`3.1.
`
`5.2.
`5.2.1.
`
`Physicochemical characteristics of the active ingredient
`Solubility.
`Solubility in hydrophilic solvents (ethanol, isopropanol, 1,2-propyleneglycol,
`glycerol, polyethylene glycol 300, acetone, etc.).
`Solubility in lipophilic solvents (chloroform, propellents (fluorinated hydrocar-
`bons) methylene chloride, vegetable oils, isopropyl myristate, etc.).
`Dependence ofsolubility 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).
`
`Analytical data on the active ingredient
`Analytical purity data (see 1.1.1.1—1.4,).
`Qualitative analytical data (see 1.1.1.1—1.6.).
`Quantitative analytical data (see 1.1.1.1.-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.
`i
`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
`thermostatin closed vessels at 50°C for 10 days. Data before andafter treatment
`are evaluated to select the most desirable buffer additive, if needed.
`Optimal humidity is determined accordingto the stability test results obtained
`from studies of samples at various humidity conditions.
`Comment: Samplesafter tests 4.1., 4.2., and 4.3. must undergo semi-quantitative
`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/cm?), heat, drying and moisture.
`Qualitative chemicalstability.
`Light stability. Against natural light: stability is determined by measuring the
`chemical changes which a sample undergoes whenirradiated for 10 days by a
`150 W xenon lampat a distance of 40 cm. The temperature should ‘not exceed
`15°C. Against UV-light (see 1.1.1.1-4.2.1,.
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2013 Page 9
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 9
`
`

`

`
`
`5.2.2.
`
`$.2.3.
`5.3.
`5.4.
`
`5.5.
`
`5.7.
`
`6.1.
`6.1.1.
`6.1.2.
`6.1.3.
`6.1.4.
`
`6.2.1.
`
`6.2.2,
`
`6.3.1.
`
`Thermalstability. It is advisable to test at least 3 dispersionsofdifferent humidity
`by storing them at 40, 50 and 60°Cfor a period of 30 days.
`:
`Determination of susceptibility to oxidation.
`Quantitative chemical stability (determination of expiration date).
`Microbiological stability. Bacteria count determinationof 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 1.1.1.1-4.5)).
`Therapeutica! stability (see 1,1.1.1.-4.6.).
`Stabilization experiments.
`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 operationalsteps, etc.).
`Diagram andinterval 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.
`Changesofthe 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.
`Directions for storage and packaging
`Health and accident prevention provisions
`
`6.3.2.
`
`71.
`TAAL.
`7.1.2.
`7.1.3.
`7.2.
`73.
`74.
`TAA.
`7A2.
`74,3.
`TAA.
`
`TAS,
`7.5,
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2013 Page 10
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 10
`
`

`

`1.1.1.3. HETEROGENEOUSFLUID- AND SEMI-SOLID-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 volumeof 100 g substance). Volume weight(the weight of
`100 cm? substance).
`1.4. Density.
`1.5. Colour, odour, taste, consistency.
`1.6. Viscosity.
`
`2.
`21.
`
`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 (ie. carriers in suppositories,
`ointments, etc.).
`2.2. Melting point.
`2.3. Wettability (Enslin number).
`2.4.
`pK of the active ingredient.
`3.
`Analytical data about the active ingredient
`3.1, Analytical purity data (see 1.1.1.1.—-1.4).
`3.2. Qualitative analytical data (see 1.1.1.1—-1.6).
`3.3. Quantitative analytical data (see 1.1.1.1—-1.7,).
`4.
`Compatibility testing. During controltesting, in addition to the normaltests,
`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.
`41. Examination of drug-druginteractions.
`42. Examination of drug-excipient interactions.
`43. Examination of interactions among excipients.
`5.
`Stability testing. It is desirable to carry outstability testing with samples of
`optimum composition.
`Physical stability.
`5.1.
`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
`(m.p.).
`52.3. Examination of susceptibility to oxidation.
`53. Quantitative chemical stability. The expiration date of the active ingredientis
`determinedon thebasis of principles of reaction kinetics with the measurement
`of specific decomposition products.
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2013 Page 11
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 11
`
`

`

`54. 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.
`6.
`Formula and working directions for the production of the drug
`6.1. Composition data.
`6.1.1. Actual composition 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, Pharmacokinetic 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
`centof all conventional dosage formulations. In the case of less common drug forms
`which were not discussed,e.g., the aerosols, additional pre-formulation aspects must
`
`
`
`
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2013 Page 12
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 12
`
`

`

`also be considered(e.g., solubility and dissolution rate of the drug in the propellent,
`determination offilm 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 1930s pharmaceutical industry has spent mostofits 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-dependentfactors 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 pre-formulation and formulation
`examination of long-acting pharmaceutical dosage formsdiffers 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 ofits 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 andtissues,
`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.
`Pharmacokinetic 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
`us time
`vs time
`vs time
`vs time
`vs time
`
`
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2013 Page 13
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 13
`
`

`

`
`
`1.3.2. Quantitative relationship of pharmacologicalactivity 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 pharmacokinetic parameters for a sustained release
`formulation.
`
`Biopharmaceutical examinations
`2.
`2.1. Determination of the dissolution rate of the drug andits 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.
`In vitro absorption rate experiments andits relationship to pH.
`2.3.
`Selective optimization of methods for reducing the dissolution rate of a given
`drug with regard to production possibilities.
`2.4. Biopharmaceutical characterization of pharmaceutical dosage form (dissolution
`tate, absorption rate, etc.).
`Instructions and proposals for drug production
`3.
`3.1. 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 comparetoxicities.
`5.2. Comparative pharmacokinetic experiments in humans to determine the absorp-
`tion and activity of the very long-acting dosage form.
`5.3. Determination ofthe bioavailability of the drug in this dosage form.
`5.3.1. Data on the relative onset of action.
`3.3.2. Data on the relative duration ofaction.
`6.
`Directions for storage and packaging of the drug formulation
`7.
`Health and accident prevention provisions
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2013 Page 14
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 14
`
`

`

`1.2. DRUG FORMULATION
`
`Numeroussteps are involved in developing a therapeutically active compoundinto
`a marketable drug product.Initial pre-formulation 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 developmentof
`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 natureofthe final product, as well as the economicfeasibility
`of large-scale production. These experiments must be carefully designed to collect
`this information in a timely manner. The primary purposeofthis chapteris 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.
`
`13.1. ESTABLISHING THE LEVEL OF SIGNIFICANCE
`
`Pre-formulation studies should be designed to provide objective experimental
`results. For example, controversial data may be foundin theliterature 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 experimentalresults. It is evident that wheneverdata are analysed
`in an experiment, a level of statistical significance must be established in order to
`correctly and logically interpret the data.
`Subjective evaluation ofdata may be sufficientif 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 always apply to a more complicated practical situation [6].
`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2013 Page 15
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2013 Page 15
`
`

`

`
`
`CHAPTER3
`
`PHYSICOCHEMICAL
`INTERACTIONS ENCOUNTERED
`IN THE COURSE
`OF DRUG PRODUCT PREPARATION
`
`3.1. GENERAL ASPECTS,
`BASIC PRINCIPLES AND DEFINITIONS
`
`The major objective of research and development in pharmaceutical technolo