20 October 2011
`EMA/CHMP/484377/2011
`Committee for Medicinal Products for Human Use (CHMP)
`
`
`
`
`CHMP assessment report
`
`
`Ameluz
`
`
`
`International non-proprietary name: 5-aminolaevulinic acid
`
`
`
`Procedure No. EMEA/H/C/002204
`
`
`
`
`Note
`
`Assessment report as adopted by the CHMP with all information of a commercially confidential nature
`deleted
`
`An agency of the European Union
`
` 7
`
` Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom
`Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455
`E-mail info@ema.europa.eu Website www.ema.europa.eu
`
`
`
`
`

`

`
`
`Ameluz
`
`
`Biofrontera Bioscience GmbH
`Hemmelrather Weg 201
`D-51377 Leverkusen
`Germany
`
`
`5-aminolaevulinic acid hydrochloride
`
`
`
`5-aminolaevulinic acid
`
`
`
`Sensitizers used in photodynamic/radiation therapy
`(L01XD04)
`
`Treatment of actinic keratosis of mild to moderate
`intensity on the face and scalp (Olsen grade 1 to 2;
`see section 5.1)
`
`
`
`Gel
`
`
`78 mg/g
`
`
`Cutaneous use
`
`
`tube (alu)
`
`
` 1
`
` tube
`
`Product information
`
`
`
`
`Name of the medicinal product:
`
`
`Applicant:
`
`
`
`Active substance:
`
`
`International Non-proprietary
`Name/Common Name:
`
`
`Pharmaco-therapeutic group
`(ATC Code):
`
`
`Therapeutic indication:
`
`
`
`Pharmaceutical form:
`
`
`Strength:
`
`
`Route of administration:
`
`
`Packaging:
`
`
`Package size:
`
`
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`CHMP assessment report
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`Table of contents
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`............................................ 6
`1.
`Background information on the procedure
`1.1 Submission of the dossier..................................................................................... 6
`1.2 Steps taken for the assessment of the product ........................................................ 7
`2.
`.............................................................................. 7
`Scientific discussion
`2.1 Introduction ....................................................................................................... 7
`2.2 Quality aspects ................................................................................................... 9
`2.2.1 Introduction .................................................................................................... 9
`2.2.2 Active Substance.............................................................................................. 9
`2.2.3 Finished Medicinal Product ............................................................................... 11
`2.2.4 Discussion on chemical, pharmaceutical and biological aspects.............................. 14
`2.2.5 Conclusions on the chemical, pharmaceutical and biological aspects ...................... 14
`2.2.6 Recommendations for future quality development ............................................... 14
`2.3 Non-clinical aspects ........................................................................................... 14
`2.3.1 Introduction .................................................................................................. 14
`2.3.2 Pharmacology ................................................................................................ 15
`2.3.3 Pharmacokinetics ........................................................................................... 18
`2.3.4 Toxicology..................................................................................................... 19
`2.3.5. Ecotoxicity/environmental risk assessment........................................................ 23
`2.3.6. Discussion and conclusion on the non-clinical aspects ......................................... 23
`2.4 Clinical aspects ................................................................................................. 24
`2.4.1 Introduction .................................................................................................. 24
`2.4.2 Pharmacokinetics ........................................................................................... 25
`2.4.3 Pharmacodynamics......................................................................................... 26
`2.4.4 Discussion and conclusions on clinical pharmacology ........................................... 26
`2.5 Clinical efficacy ................................................................................................. 26
`2.5.1 Dose response study....................................................................................... 27
`2.5.2 Main studies .................................................................................................. 28
`2.5.3 Discussion on clinical efficacy ........................................................................... 43
`2.5.4 Conclusions on the clinical efficacy .................................................................... 43
`2.6 Clinical safety ................................................................................................... 43
`2.6.1 Discussion on clinical safety ............................................................................. 52
`2.6.2 Conclusions on the clinical safety ...................................................................... 53
`2.7 Pharmacovigilance ............................................................................................ 53
`2.8 User consultation .............................................................................................. 54
`3.
`........................................................................... 55
`Benefit-Risk Balance
`4.
`............................................................................... 56
`
`
`
`Recommendations
`
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`

`List of abbreviations
`
`percent
`
`
`
`%
`infinity
`
`
`
`∞
`1O2
` singlet oxygen
`
`
`
`5-fluorouracil
`
`5-FU
`
`
`alternative hypothesis
`
`A1
`AE adverse event
`AK
`
`
`
`actinic keratosis
`ALA
`
`
`
`5-aminolaevulinic acid
`ALAD aminolaevulinic acid dehydratase
`ATP adenosine triphosphate
`BMI
`
`
`
`body mass index
`χ2
`
`
`
`chi square
`C
`
`
`
`Caucasian
`CCCR
`
`
`complete clinical clearance rate
`CI
`
`
`
`confidence interval
`cm
`
`
`
`centimetre
`cm2
`
`
`
`square centimetre
`CHMP
`
`
`Committee for Human Medicinal Products
`CR
`
`
`
`clearance rate
`EC
`
`
`
`Ethics committee
`e.g. exempli gratia,
`
`for example
`EMA
`
`
`European Medicines Agency
`EU
`
`
`
`European Union
`F
`
`
`
`women
`FAS
`
`
`
`full-analysis set
`g
`
`
`
`gram
`μg
`
`
`
`microgram
`GCP
`
`
`
`Good Clinical Practice
`GLP
`
` Good Laboratory Practice
`H
`
`
`
`hour
`H0
`
`
`
`null hypothesis
`H1
`
`
`
`(alternative) hypothesis
`HIV
`
`
`
`Human immunodeficiency virus
`ICH
`
`
`
`International Conference on Harmonization
`i.e.
`
`
`
`id est, that is
`ITT
`
`
`
`intent-to-treat
`J
`
`
`
`Joule
`kg
`
`
`
`kilogram
`LOCF last observation carried forward
`M
`
`
`
`men
`m2
`
`
`
`square meter
`mm
` millimetre
`mm2
`
`
`
`square millimetre
`
`MAL
`
`
`methyl-aminolaevulinic acid
`MedDRA
`
`
`Medical Dictionary for Regulatory Activities
`mg
`
`
`
`milligram
`μg
`
`
`
`microgram
`mL
`
`
`
`millilitre
`mW
`
`
`
`milliwatt
`n
`
`
`
`number
`N/A
`
`
`
`not applicable
`nm
`
`
`
`nanometre
`OR
`
`
`
`odds ratio
`P
`
`
`
`probability
`PBG porpobilinogen
`PDT
`
`
`
`photodynamic therapy
`PK pharmacokinetics
`PP
`
`
`
`per-protocol
`PpIX
`
`
`
`protoporphyrin IX
`r
`
`
`
`randomized
`
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`
`
`Respectively
`
`
`Resp
` reactive oxygen species
`ROS
`
`
`second
`
`sec
`
`
`squamous cell carcinoma
`
`SCC
`
`
`standard deviation
`
`SD
`
`
`solar keratosis
`
`SK
` Summary of Product Characteristics
`SmPC
`
`
`face and forehead
`Target area A
`
`
`bald scalp
`Target area B
`TEAE treatment emergent adverse event
`U
`
`
`
`unit
`UV ultraviolet
`vs.
`
`
`
`versus, as opposed to
`
`
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`1. Background information on the procedure
`
`1.1 Submission of the dossier
`
`The applicant Biofrontera Bioscience GmbH submitted on 2 September 2010 an application for
`Marketing Authorisation to the European Medicines Agency (EMA) for Ameluz, through the centralised
`procedure under Article 3 (2) (b) of Regulation (EC) No 726/2004. The eligibility to the centralised
`procedure was agreed upon by the EMA/CHMP on 25 September 2008. The eligibility to the centralised
`procedure under Article 3(2) (b) of Regulation (EC) No 726/2004 was based on demonstration of
`significant technical innovation.
`
`The applicant applied for the following indication: treatment of actinic keratosis of mild to moderate
`intensity on the face and scalp (Olsen grade 1 to 2).
`
`The legal basis for this application refers to:
`
`Article 8.3 of Directive 2001/83/EC.
`
`The application submitted is composed of administrative information, complete quality data, non-
`clinical and clinical data based on applicants’ own tests and studies and/or bibliographic literature
`substituting/supporting certain tests or studies.
`
`Information on Paediatric requirements
`
`Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA Decision
`P/157/2009 on the granting of a (product-specific) waiver.
`
`Information relating to orphan market exclusivity
`
`Similarity
`
`Not applicable.
`
`Scientific Advice
`
`The applicant did not seek scientific advice at the CHMP.
`
`Licensing status
`
`The product was not licensed in any country at the time of submission of the application.
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`1.2 Steps taken for the assessment of the product
`
`The Rapporteur and Co-Rapporteur appointed by the CHMP were:
`
`Rapporteur: Harald Enzmann
`
`Co-Rapporteur: Patrick Salmon
`
`
`
`
`
`
`
`The application was received by the EMA on 2 September 2010.
`
`The procedure started on 22 September 2010.
`
`The Rapporteur's first Assessment Report was circulated to all CHMP members on 10 December
`2010. The Co-Reporter’s first Assessment Report was circulated to all CHMP members on 13
`December 2010.
`
` During the meeting on 17-20 January 2011, the CHMP agreed on the consolidated List of Questions
`to be sent to the applicant. The final consolidated List of Questions was sent to the applicant on 21
`January 2011.
`
`
`
`
`
`The applicant submitted the responses to the CHMP consolidated List of Questions on 20 May 2011.
`
`The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of
`Questions to all CHMP members on 6 July 2011.
`
` During the CHMP meeting on 21 July 2011, the CHMP agreed on a List of outstanding issues to be
`addressed in writing by the applicant.
`
`
`
`
`
`The applicant submitted the responses to the CHMP List of Outstanding Issues on 19 September
`2011.
`
`The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of
`outstanding issues to all CHMP members on 6 October 2011.
`
` During the meeting on 17-20 October 2011, the CHMP, in the light of the overall data submitted
`and the scientific discussion within the Committee, issued a positive opinion for granting a
`Marketing Authorisation to Ameluz on 20 October 2011.
`
`
`
`2. Scientific discussion
`
`2.1 Introduction
`
`Problem statement
`
`Actinic keratosis (AK) is an ultraviolet-light-induced lesion of the skin that may progress to invasive
`squamous cell carcinoma (Glogau, 2000). It is the most common lesion with malignant potential to
`arise on the skin. AK is mostly seen in fair-skinned persons on skin areas that have had long-term sun
`exposure (Salasche, 2000).
`
`Epidemiological data show a high occurrence rate of AK. Regions with higher ultraviolet exposure have
`a higher prevalence of AK. In Europe, a prevalence of 15% in men and 6% in women has been
`documented. Over the age of 70 years, 34% of men and 18% of women were found to have AK
`(Memon et al., 2000).
`
`An AK may regress, persist unchanged, or progress to invasive squamous cell carcinoma. The actual
`percentage that progress to invasive SCC remains unknown, and estimates vary from 5% to 20%
`within 10 to 25 years with reported annual transformation rate ranging widely from as low as 0.25% to
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`as high as 16% (Braathen et al., 2007). Furthermore, predicting which course each individual lesion
`will follow is impossible.
`
`AK treatment options belong to 2 broad categories: surgical destruction of the lesions (e.g. using
`cryosurgery or curettage with or without electrosurgery) and medical therapy. Medicinal products
`approved in the EU include 5-fluorouracil cream, imiquimod cream, diclofenac gel, and photodynamic
`therapy (PDT) with 5-aminolaevulinic acid (ALA) or methyl-aminolaevulinic acid (MAL).
`
`Two products containing ALA or ALA derivates have been available since several years. The two ALA-
`PDT products use different ways to address the problem around the inherent instability of ALA in
`aqueous formulations. Levulan is provided as a 2-component system to be mixed immediately before
`use, ALAcare takes advantage of the attachment of solid ALA crystals to the plaster (Hauschild et al.,
`2009) and Metvix uses the more stable methyl-ester derivative MAL.
`
`A second drawback is the fact that ALA is a dipolar ion at physiologic pH with low lipid solubility and
`limited ability to penetrate the stratum corneum. The use of more lipophilic ALA derivatives such as
`MAL is an attempt to overcome this problem, but skin penetration is only improved with esters with an
`even higher number of carbon ions (≥C4). Short-chained ALA-esters (C1-C3) induced 5 to 10 times
`lower PpIX accumulation than ALA as shown in several cell lines (Gaullier et al., 1997).
`
`The rationale to develop Ameluz was to provide a novel ALA formulation for PDT which increases the
`stability of the active ingredient and improves the delivery of the active ingredient into the target cells
`of the AK lesions within the epidermis.
`
`About the product
`
`Ameluz (known as BF-200 ALA) is a gel formulation containing ALA in a nanoemulsion developed for
`topical treatment of actinic AK in combination with PDT. The nanoemulsion formulation provides
`chemical stabilization of ALA and enhances its penetration into the epidermis.
`
`Following topical application of 5-aminolaevulinic acid, the substance is metabolized to protoporphyrin
`IX, a photoactive compound which accumulates intracellularly in the treated actinic keratosis lesions.
`Protoporphyrin IX is activated by illumination with red light of a suitable wavelength and energy. In the
`presence of oxygen, reactive oxygen species are formed. The latter causes damage of cellular
`components and eventually destroys the target cells.
`
`The Applicant applied for the indication: Treatment of actinic keratosis of mild to moderate intensity on
`the face and scalp (Olsen grade 1 to 2). The finally approved indication was: Treatment of actinic
`keratosis of mild to moderate intensity on the face and scalp (Olsen grade 1 to 2; see section 5.1 of
`the SmPC).
`
`The gel should cover the lesions and approximately 5 mm of the surrounding area with a film of about
`1 mm thickness. The entire treatment area will be illuminated with a red light source, either with a
`narrow spectrum around 630 nm and a light dose of approximately 37 J/cm2 or a broader and
`continuous spectrum in the range between 570 and 670 nm with a light dose between 75 and
`200 J/cm2.
`
`One session of photodynamic therapy should be administered for single or multiple lesions. Actinic
`keratosis lesions should be evaluated three months after treatment. Non- or partially responding
`lesions should be re-treated in a second session. The gel should cover the lesions and approximately
`5 mm of the surrounding area with a film of about 1 mm thickness. The entire treatment area will be
`illuminated with a red light source, either with a narrow spectrum around 630 nm and a light dose of
`approximately 37 J/cm2 or a broader and continuous spectrum in the range between 570 and 670 nm
`with a light dose between 75 and 200 J/cm2. It is important to ensure that the correct light dose is
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`administered. The light dose is determined by factors such as the size of the light field, the distance
`between lamp and skin surface, and the illumination time. These factors vary with lamp type. The light
`dose delivered should be monitored if a suitable detector is available.
`
`Before administration of Ameluz scales and crusts should be removed accurately. In addition, all lesion
`surfaces should be roughened gently. Care should be taken to avoid bleeding. Thereafter, all lesions
`should be carefully wiped-off with an ethanol or isopropanol-soaked cotton pad to ascertain degreasing
`of the skin.
`
`Ameluz should be applied to the entire lesion area using glove protected fingertips or a spatula. The
`gel can be administered to healthy skin around the lesions, whereas application near the eyes, nostrils,
`mouth, ears or mucosa should be avoided (keep a distance of 1 cm). Direct contact of Ameluz with the
`eyes or mucous membrane should be avoided. In case of accidental contact, rinsing with water is
`recommended. The gel should be allowed to dry for approximately 10 minutes, before an occlusive
`light-tight dressing is placed over the treatment site. Following 3 hours of incubation, the dressing
`should be removed and the remnant gel wiped off.
`
`Immediately after cleaning the lesions, the entire treatment area will be illuminated with a red light
`source. During illumination the lamp should be fixed at the distance from the skin surface that is
`indicated in the user manual. A narrow spectrum lamp is recommended to achieve higher clearance
`rates. Symptomatic treatment of transient adverse site reactions may be considered. A broader and
`continuous spectrum may be used if narrow-spectrum light sources are not tolerated.
`
`Lesions should be re-assessed after three months, at which point any residual lesions may be retreated.
`
`2.2 Quality aspects
`
`2.2.1 Introduction
`
`Ameluz 78mg/g is a gel for cutaneous use, presented in a 2g tube, for the photodynamic treatment of
`actinic keratosis of mild to moderate intensity on the face and scalp. The active substance, is 5-
`aminolaevulinic acid (as 5-aminolaevulinic acid hydrochloride), which is of synthetic chemical origin.
`
`Ameluz is a white to yellowish gel containing 78mg/g of 5-aminolaevulinic acid (as hydrochloride) filled
`in aluminium tubes with epoxyphenol inner lacquer and a latex seal and a screw cap of high density
`polyethylene.
`
`The excipients used in the preparation of Ameluz are xanthan gum, soybean phosphatidylcholine,
`polysorbate 80, medium-chain triglycerides, isopropyl alcohol, disodium phosphate dihydrate, sodium
`dihydrogen phosphate dihydrate, propylene glycol, sodium benzoate and purified water.
`
`The gel is intended to be applied to prepared skin lesions and covered with an occlusive dressing to aid
`absorption. The gel contains an o/w nanoemulsion which enhances skin penetration of the active
`substance. The active substance is metabolised within the dermis to protoporphyrin IX which
`accumulates intracellularly within the actinic keratosis lesion. The photoactive protoporphyrin IX is then
`activated by a defined CE-marked red-light source to produce reactive oxygen species which destroy
`the target cells to produce the required effect.
`
`2.2.2 Active Substance
`
`The active substance is 5-aminolaevulinic acid hydrochloride, an achiral substance which is crystalline
`and readily soluble in water, ethanol and dimethylformamide. The active substance is not covered by a
`pharmacopoeial monograph. The figure below shows the chemical structure of 5-aminolaevulinic acid
`hydrochloride.
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`
`
`O
`
`H2N
`
`OH
`
`
`
`O
`· HCl
`The octanol/water partition coefficient (P) illustrates the hydrophile/lipophile balance of 5-
`aminolaevulinic acid and has been experimentally determined as 0.03. The log P value is -1.5. No
`specific permeability studies have been carried out for 5-aminolaevulinic acid, however, the partition
`coefficient between the stratum corneum and water (KSC/W) was determined to be 0.04 (log KSC/W -
`1.37). The partition coefficient and corresponding log P values determined for 5-aminolaevulinic acid
`for octanol/water and stratum corneum/water reflect the high water solubility of 5-aminolaevulinic
`acid.
`
`
`
`Manufacture
`
`5-Aminolaevulinic acid hydrochloride is manufactured in two steps from 5N-(phthaloyl) amino-
`laevulinic acid methyl ester, consisting of ester hydrolysis and recrystalllisation of crude 5-
`aminolaevulinic acid hydrochloride. A description of the manufacture and a list of materials used for
`manufacture of 5N-(phthaloyl)amino-laevulinic acid methyl ester as well as the specification of
`laevulinic acid and the intermediate of the synthesis of 5N-(phthaloyl)amino-laevulinic acid methyl
`ester have been provided, the starting material should be redefined. A request has been included in
`the list of recommendations.
`
`Details on the control of the materials used, both for manufacture of 5N-(phthaloyl)amino-laevulinic
`acid methyl ester and the final active substance, including specifications for raw materials and details
`and justification of the control of the starting material including analytical methods and validation were
`satisfactorily provided. Details were also provided on critical in-process tests during manufacture
`together with control limits during manufacture and validation of analytical methods.
`
`The results from 1H-NMR and 13C-NMR spectra, elemental analysis and the mass spectrum are
`consistent with the structure of the active substance.
`
`Synthesis related impurities, degradation pathways and residual solvents were satisfactorily presented.
`
`Batch results were presented for six production scale batches and one pilot scale batch. All batch
`results are in accordance with the specification of 5-aminolaevulinic acid hydrochloride.
`
`Specification
`
`The active substance specification includes tests for description (visual examination), identification (IR
`spectroscopy, HPLC, test on chloride and melting point), assay (HPLC and argentometric), related
`substances (HPLC), water content (Karl Fisher), loss on drying (Ph.Eur.), sulphated ash (Ph.Eur.) and
`residual solvents (GC).
`
`The specification was found to be justified. Impurities have been evaluated and found to be acceptable
`from the point of view of safety. However, based on batch data results, the limit for the sum of total
`impurities should be further tightened once further batch experience is gained. This request is included
`in the list of recommendations.
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`All analytical procedures of the active substance were described and were generally sufficiently
`validated. However, a request for a full validation of the HPLC method applied for the control of
`impurities in the starting material, 5N-(phthaloyl) amino-laevulinic acid methyl ester, is included in the
`list of recommendations.
`
`The finished product manufacturer controls the active substance according to the specification and
`analytical procedures of the active substance manufacturer.
`
`Validation in line with ICH requirements has been carried out for the HPLC method. The validation
`included specificity for impurities from the active substance specification and those arising in the active
`substance starting material. The HPLC method was found to be stability indicating as it is able to
`detect impurities arising out of forced degradation. Range, linearity and accuracy have been
`determined for the active and specified impurities of the active substance specification. The ranges
`studied are appropriate for assay and known impurities respectively. Linearity, accuracy and
`repeatability of the assay of 5-aminolaevulinic acid were validated from 80 to 120% of label claim.
`Intermediate precision was verified at 100% of the active substance.
`
`Batch analytical data provided on six production scale batches demonstrated compliance with the
`specification and showed the active to be of good quality.
`
`Impurities have been evaluated and found to be acceptable from the point of view of safety.
`
`The reference standards for 5-aminolaevulinic acid were presented in adequate detail. Identity and
`purity of the impurity reference standards were sufficiently characterized. There is a remaining point
`for clarification regarding standards for two unspecified impurities which is included in the list of
`recommendations.
`
`Stability
`
`Long-term stability studies at -15°C, at 5°C and at 25 °C / 60% RH were performed on three
`production scale batches for 36 months. Storage at 40°C/75% RH (accelerated conditions) for 12
`months led to discoloration of the active substance and to out of specification results of related
`substances.
`
`The stability studies showed that the active substance is stable when stored in a freezer and confirm
`the proposed re-test period.
`
`Comparability exercise for Active Substance
`
`Not applicable.
`
` 2.2.3 Finished Medicinal Product
`
`Ameluz is a non-sterile gel formulation for the topical treatment of actinic keratosis lesions. It is
`presented in aluminium tubes with epoxyphenol inner lacquer and latex seals which are closed with
`screw caps made of high density polyethylene. The product is intended for single use and each tube
`contains 2g of gel. Ameluz 78mg/g gel contains 7.8% of 5-aminolaevulinic acid which is equivalent to
`10% of 5-aminolaevulinic acid hydrochloride salt.
`
`Pharmaceutical Development
`
`The active substance is hydrophilic, unstable in aqueous solutions and has limited ability to penetrate
`the outer epidermal layer (stratum corneum) which is more permeable for lipophilic compounds.
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`The objective of the pharmaceutical development was to provide a novel formulation of 5-
`aminolaevulinic acid, which increases the stability and improves the delivery of the active substance
`through the stratum corneum and into the target cells of the lesions of actinic keratosis within the
`epidermis.
`
`A gel formulation was selected, containing a nanoscale oil in water emulsion. Soybean
`phosphatidylcholine-containing nanoemulsions are able to stabilize 5-aminolaevulinic acid in the gel,
`significantly contributes to the enhancement of the permeation of 5-aminolaevulinic acid through the
`skin. Soybean-derived phospholipids have high affinities to epidermal tissue and change the skin lipid
`fluidity leading to enhanced percutaneous drug absorption. Therefore, it is possible to reduce the
`concentration of the active ingredient, while maintaining an efficient uptake of the active substance
`into neoplastic cells.
`
`The data submitted suggested that 5-aminolaevulinic acid is not included in the nanoemulsion core. 5-
`Aminolaevulinic acid is a strongly hydrophilic molecule. Therefore, it is not expected that 5-
`aminolaevulinic acid is included in the core of the nanoemulsion. Further, indirect evidence is provided
`by the cell culture experiments, which have shown that the uptake of 5-aminolaevulinic acid in cell
`culture is also increased when the nanoemulsion and 5-aminolaevulinic acid are added successively,
`indicating that the effect is not the consequence of a direct interaction of the nanoemulsion and 5-
`aminolaevulinic acid.
`
`The excipients used in the preparation of Ameluz are xanthan gum (gel forming agent), soybean
`phosphatidylcholine (surfactant), polysorbate 80 (co-surfactant), medium-chain triglycerides (lipid
`core), isopropyl alcohol (solvent), disodium phosphate dehydrate (buffering agent), sodium dihydrogen
`phosphate dehydrate (buffering agent), propylene glycol (solvent), sodium benzoate (preservative)
`and purified water (solvent). All excipients are of Ph. Eur. quality with exception of soybean
`phosphatidylcholine which is controlled for identity, purity and assay with an in-house monograph.
`
`The antimicrobial effectiveness of the preservative has been confirmed and complies with Ph. Eur.
`5.1.3 criteria A.
`
`Adventitious agents
`
`None of the excipients used in the formulation of Ameluz are of animal origin.
`
`Manufacture of the product
`
`The manufacturing process of Ameluz comprises (1) preparation of an aqueous buffer phase, (2)
`preparation of the gel phase, (3) preparation of the nanoemulsion, (4) preparation of the bulk product
`by adding the preservative, the active substance and the gel phase, (5) filling into aluminium tubes
`and secondary packaging.
`
`The critical quality attributes of the drug product appear to be the particle size and viscosity. The
`physico-chemical characterization of the drug product, including characterization of the particle size
`distribution by photon correlation spectroscopy and electron microscopy, has been sufficiently detailed.
`
`There are several in process controls such as determination of the pH of the buffer, viscosity of the gel
`phase, pH, particle size and size distribution of the nanoemulsion and the bulk product, check of the fill
`weight at the end of the filling operation. All parameters of the release specification were analysed.
`The results indicated homogeneity of macroscopic appearance, pH, viscosity, assay of active
`substance, content of preservative, related substances (specified impurities below 0.1%, unspecified
`impurities at or below 0.1%, respectively), microbial purity and filling weight. Intra-batch homogeneity
`of the nanoparticle size distribution has been confirmed on a fourth process validation batch.
`
`BF-200 ALA
`CHMP assessment report
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`Page 12/57
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`Nonetheless, further data should be generated documenting intra-batch homogeneity with regard to
`the particle size of the nanovesicles for the first two batches to be manufactured after granting of the
`marketing authorisation. This request is included in the list of recommendations.
`
`
`
`Three full scale batches were manufactured using the same manufacturing facilities, manufacturing
`process and same equipment as the batches intended for marketing. The batches fully met the quality
`control specifications, and results of IPC and additional testing show that the manufacturing process is
`robust. Each of the drug product batches was manufactured with a different batch of the drug
`substance. Therefore it can be concluded that the batches can be manufactured reproducibly at
`commercial scale.
`
`Product specification
`
`The specification for Ameluz includes tests for appearance (visual examination), identification of 5-
`aminolaevulinic acid (HPLC and TLC), identification of sodium benzoate (HPLC), assay of 5-
`aminolaevulinic acid and sodium benzoate (HPLC), extractable mass, pH (Ph.Eur.), viscosity
`(vibroviscosimetry), particle size (laser light scattering), related substances (HPLC-MS) and microbial
`purity (Ph.Eur.).
`
`The release and shelf-life specification for the drug product were found to be justified. However, based
`on batch data results, the limit for the sum of total impurities should be further tightened in line with
`long term stability results. In addition, the shelf life limit for a specified impurity should be tightened
`when further batch data become available. These requests are included in the list of recommendations.
`
`
`
`All methods have been satisfactorily validated. The HPLC method has been validated for specificity,
`linearity, range, accuracy, intermediate precision and robustness. The validation data demonstrated
`that the method is suitable for the identification and assay test of 5-aminolaevulinic acid hydrochloride.
`For methods described in the Ph. Eur. validation was deemed to be unnecessary. The microbial purity
`of the drug product was compliant with Ph. Eur. requirements for preparations for cutaneous use.
`
`Stability of the product
`
`The stability of the drug product has been investigated with three production scale batches from the
`manufacturer proposed for marketing. The batches were stored in the packaging as proposed for
`manufacture in