24 June 2010
`EMA/CHMP/450053/2010
`
`Evaluation of Medicines for Human Use
`
`
`
`
`CHMP assessment report
`
`
`Ruconest
`
`
`
`International Nonproprietary Name: conestat alfa
`
`
`
`Procedure No. EMEA/H/C/001223
`
`
`
`
`
`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
`
`
`
`European Medicines Agency, 2010. Reproduction is authorised provided the source is acknowledged.
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`Page 1 of 57
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`CSL EXHIBIT 1041
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`

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` Table of contents
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`Page
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`1. Background information on the procedure .............................................. 3
`1.1. Submission of the dossier.................................................................................... 3
`1.1.1. For new centralised dossiers orphan medicinal products ........................................ 3
`1.1.2. Information on paediatric requirements .............................................................. 3
`1.1.3. Information relating to orphan market exclusivity ................................................ 3
`1.1.4. Licensing status: ............................................................................................. 4
`1.2. Steps taken for the assessment of the product ....................................................... 4
`2. Scientific discussion ................................................................................ 4
`2.1. Introduction ...................................................................................................... 4
`2.2. Quality aspects .................................................................................................. 6
`2.2.1. Introduction ................................................................................................... 6
`2.2.2. Active substance ............................................................................................. 7
`2.2.3. Finished Product.............................................................................................. 9
`2.3. Non-clinical aspects .......................................................................................... 10
`2.3.1. Introduction ................................................................................................. 10
`2.3.2. Pharmacology ............................................................................................... 11
`2.3.3. Pharmacokinetics .......................................................................................... 11
`2.3.4. Toxicology.................................................................................................... 13
`2.3.5. Ecotoxicity/environmental risk assessment........................................................ 17
`2.3.6. Discussion on non-clinical aspects.................................................................... 17
`2.3.7. Conclusion on the non-clinical aspects .............................................................. 18
`2.4. Clinical aspects ................................................................................................ 18
`2.4.1. Introduction ................................................................................................. 18
`2.4.2. GCP............................................................................................................. 20
`2.4.3. Pharmacokinetics .......................................................................................... 20
`2.4.4. Pharmacodynamics........................................................................................ 22
`2.4.5. Discussion on clinical pharmacology ................................................................. 23
`2.4.6. Conclusions on clinical pharmacology ............................................................... 24
`2.4.7. Clinical efficacy ............................................................................................. 24
`2.4.8. Discussion on clinical efficacy .......................................................................... 41
`2.4.9. Conclusions on the clinical efficacy ................................................................... 43
`2.4.10. Clinical safety.............................................................................................. 43
`2.5. Discussion on clinical safety............................................................................... 48
`2.6. Conclusions on the clinical safety........................................................................ 49
`2.7. Pharmacovigilance............................................................................................ 49
`2.7.1. Detailed description of the pharmacovigilance system......................................... 49
`2.7.2. Risk management plan................................................................................... 49
`2.7.3. Benefit-risk balance ....................................................................................... 54
`2.7.4. Similarity with authorised orphan medicinal products.......................................... 57
`2.7.5. Recommendation........................................................................................... 57
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`Page 2 of 57
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`1. Background information on the procedure
`
`1.1. Submission of the dossier
`
`The applicant Pharming Group N.V. submitted on 03 September 2009 an application for Marketing
`Authorisation to the European Medicines Agency for Ruconest, through the centralised procedure falling
`within the Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004. The eligibility to the
`centralised procedure was agreed upon by the Agency/CHMP on 27 April 2006.
`
`
`
`The legal basis for this application refers to:
`
`Article 8.3 of Directive 2001/83/EC, as amended - complete and independent application
`
`The application submitted is a complete dossier composed of administrative information, complete
`quality data, non-clinical and clinical data based on applicants’ own tests and studies
`
`
`
`The applicant applied for the following indication:
`
`Treatment of acute angioedema attacks in adults with hereditary angioedema (HAE) due to C1
`esterase inhibitor deficiency.
`
`1.1.1. For new centralised dossiers orphan medicinal products
`
`The applicant Pharming Group N.V. submitted on 03 September 2009 an application for Marketing
`Authorisation to the European Medicines Agency through the centralised procedure for Ruconest, which
`was designated as an orphan medicinal product EU/3/01/036 on 11 May 2001. Ruconest was
`designated as an orphan medicinal product in the following indication: Treatment of angioedema
`caused by C1 inhibitor deficiency. The calculated prevalence of this condition was approximately 2.1 in
`10,000 EU population.
`
`In connection with the review of the orphan designation criteria by the Committee on Orphan Medicinal
`Products (COMP) at its meeting of 7-8 September 2010, the Applicant requested the Commission to
`remove the product from the Community Register of Orphan Medicinal Products on 9 September 2010.
`
`1.1.2. Information on paediatric requirements
`
`Pursuant to Article 7, of Regulation (EC) No 1901/2006 the application included an Agency Decision
`P/132/2009 for the following condition:
`
`Hereditary angioedema
`
`on the agreement of a paediatric investigation plan (PIP).
`
`The PIP is not yet completed.
`
`1.1.3. Information relating to orphan market exclusivity
`
`1.1.3.1. Similarity
`
`Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No
`847/2000, the application contained a critical report addressing the possible similarity with authorised
`orphan medicinal products.
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`1.1.3.2. Protocol assistance
`
`The applicant received Protocol Assistance from the CHMP on 21 November 2003. The Protocol
`Assistance pertained to quality, non-clinical and clinical aspects of the dossier.
`
`1.1.4. Licensing status:
`
`The product was not licensed in any country at the time of submission of the application.
`
`The Rapporteur and Co-Rapporteur appointed by the CHMP and the evaluation teams were:
`
`Rapporteur:
`
`Ian Hudson
`
` Co-Rapporteur:
`
`Kristina Dunder
`
`1.2. Steps taken for the assessment of the product
`
`•
`•
`•
`
`•
`
`•
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`The application was received by the Agency on 03 September 2009.
`The procedure started on 23 September 2009.
`The Rapporteur's first Assessment Report was circulated to all CHMP members on 11 December
`2009. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 11
`December 2009.
`• During the meeting on 18-21 January 2010, 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 2010.
`The applicant submitted the responses to the CHMP consolidated List of Questions on 18 March
`2010.
`The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of
`Questions to all CHMP members on 30 April 2010.
`• During the CHMP meeting on 17-20 May 2010, 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 consolidated List of Outstanding Issues on
`24 May 2010.
`The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of
`Outstanding Issues to all CHMP members on 7 June 2010.
`• During the meeting on 21-24 June, 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 Ruconest on 24 June 2010. The applicant provided the letter of undertaking on the
`follow-up measures to be fulfilled post-authorisation on 23 June 2010.
`• On 9 September 2010 the applicant requested the Commission to remove the product from the
`Community Register of Orphan Medicinal Products.
`
`•
`
`•
`
`For new centralised dossiers orphan medicinal products
`
`The CHMP adopted a report on similarity of Ruconest with Firazyr on 21 January 2010.
`
`•
`
`Note: The product was previously known as Rhucin.
`
`
`
`2. Scientific discussion
`
`2.1. Introduction
`
`C1 inhibitor (C1INH), a serine proteinase inhibitor (serpin), is primarily synthesized in the liver and the
`normal range of C1INH activity in the general population is 0.7 to 1.3 U/mL (70 to 130%). The main
`function of C1INH is inhibition of several complement proteinases and contact-system proteinases.
`
`Hereditary angioneurotic oedema (HAE) is characterized by recurrent, often unpredictable, acute
`attacks of soft tissue swelling (angioedema). Acute angioedema attacks in HAE patients impair the
`quality of life, and can be fatal if the angioedema swelling occurs in the throat. An untreated attack can
`persist for up to five days. Attacks of oedema of the gastrointestinal tract are associated with severe
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`pain similar to acute abdominal syndromes and may cause nausea, vomiting, diarrhoea, ascites and
`symptoms of hypovolemia.
`
`Two types of congenital functional C11NH deficiency (phenotypic variants) can be distinguished (HAE
`Type I and HAE Type II). Both types are autosomal dominant disorders and the levels of functional
`C11NH in plasma are below 50% of normal
`levels. The median plasma level of C11NH activity in
`patients with HAE is about 0.2 U/mL, or 20% of the level found in healthy individuals
`
`Key inflammatory mediators regulated by C1INH of concern for patients with HAE include activated
`proteases of the complement system such as C1r, C15 and Mannan Binding protein (MBP)-associated
`proteinases (MASPs), and factor XIIa, factor XIa and kallikrein of the contact system (Figure 1). Over
`activity of these inflammatory proteases is thought to lead to the generation of vasoactive peptides
`such as bradykinin that mediate angioedema attacks.
`
`Negatively
`
`charged
`
`
`Contact system
`
`surface
`
`FXII —’ FXIIa
`
`Complement system
`
`Prekallikrein ‘ C1
`
` C42
`Kallikrein
`c1 rs L.
`
`
`Wen_ ’
`
`l
`BK2R
`
`W
`
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`Fibrinolytic system
`
`Plasmin
`
`Figure 1. Schematic picture showing the C1INH mechanism of action.
`
`The current available treatments of acute attacks of HAE include:
`
`. Human C11NH preparations, which are purified and pasteurized concentrates from pooled
`human plasma (one approved in most EU member states via the Mutual Recognition
`Procedure, one is approved in the Netherlands);
`Icatibant (approved through the centralised procedure), which acts as a selective competitive
`antagonist at the bradykinin type 2 (32) receptor.
`
`.
`
`Conestat alfa, the active substance of Ruconest, a recombinant human component 1 (C1) esterase
`inhibitor (rhC1INH),
`is the recombinant analogue of human C1 esterase inhibitor (C1INH), and is
`obtained from the milk of rabbits expressing the gene encoding for human C11NH. The transgenic
`rabbits, which are genetically modified organisms (GMO), are maintained in specific pathogen free
`enclosed housings. The product, however,
`is not a GMO. The availability of a non-blood product
`derived C11NH for treatment of acute attacks of HAE provides a further treatment option for patients.
`
`The applicant Pharming Group N.V. submitted a complete and independent application for Marketing
`Authorisation to the European Medicines Agency for Ruconest (previously known as Rhucin) for
`treatment of acute angioedema attacks in adults with hereditary angioedema (HAE) due to C1 esterase
`inhibitor deficiency.
`
`Ruconest was designated as an orphan medicinal product in the EU with the following orphan indication:
`treatment of angioedema caused by C1 inhibitor deficiency. HAE was considered as chronically
`debilitating conditions, characterised by acute and repetitive attacks, which might be life-threatening.
`The calculated prevalence of this condition at the time or orphan medicinal product designation was
`
`CHMP assessment repout
`EMA/CHMP/450053/2010
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`Page 5 0f 57
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`2.1 per 10,000 EU population. The significant benefit at the time of designation was based on major
`contribution to patient care with regards to currently authorised medicinal products on the basis of a
`source of non-blood derived C1INH.
`
`In connection with the review of the orphan designation criteria by the Committee on Orphan Medicinal
`Products (COMP) at its meeting of 7-8 September 2010, the Applicant requested the Commission to
`remove the product from the Community Register of Orphan Medicinal Products on 9 September 2010.
`
`The applicant received Protocol Assistance from the CHMP on the quality, preclinical and clinical
`development. There are no guidelines on the evaluation of medicinal products for the treatment of
`acute HAE attacks. The primary and secondary endpoints used in the two RDCT 1205 and 1304 are
`mainly in line with the Protocol Assistance given by the CHMP.
`
`With regard to the paediatric development, the applicant has agreed to generate data in paediatric
`patients aged 2-18 years; these data are not yet available and will need to be provided post-
`authorisation. Studies in patients under 24 months are not requested.
`
`This is the second marketing authorisation application (MAA) submitted for this medicinal product. The
`first MAA was submitted in July 2006 and received a negative opinion on the basis of the limited clinical
`database and concerns regarding severe allergic reactions and the potential for immunogenicity
`following repeated administrations. Additional clinical data for the present application for the present
`MAA was submitted with two finalised placebo-controlled studies and data from the ongoing extension
`phases of the two open-label studies. The current data also specifically addresses immunogenicity,
`efficacy in laryngeal attacks, and the possibility of thrombogenic potential. Furthermore, a new dose
`regimen was proposed.
`
`The applicant initially applied for the following indication:
`“Ruconest is indicated for treatment of acute angioedema attacks in patients with hereditary
`angioedema (HAE) due to C1 esterase inhibitor deficiency”
`
`The finally approved indication is as follows:
`“Ruconest is indicated for treatment of acute angioedema attacks in adults with hereditary angioedema
`(HAE) due to C1 esterase inhibitor deficiency.”
`
`The product is administered by intravenous injection. The posology is one single dose of 50 U/kg body
`weight for adults up to 84 kg body weight or 4200 U for adults of 84 kg body weight and above.
`
`2.2. Quality aspects
`
`2.2.1. Introduction
`
`C1 inhibitor (C1INH) is a serine protease inhibitor belonging to the serpin superfamily. The active
`substance of Ruconest is a recombinant analogue of human C1INH (rhC1INH, INN: conestat alfa) that
`is purified from the milk of rabbits expressing the gene encoding for human C1INH. It is a plasma
`single-chain glycoprotein containing 478 amino acids with six sites of N-glycosylation and at least
`seven sites of O-glycosylation. It has a molecular mass of approximately 67,000 Da of which
`approximately 22% is due to oligosaccharides. The amino acid sequence has been provided and
`includes two disulphide bonds (between cys101- cys406 and cys108 - cys183).
`
`The drug product is presented as a powder for solution for injection. It is a sterile, non-pyrogenic,
`preservative-free, white to off-white lyophilized powder contained in a single-use type I, colourless
`sealed glass vial. The product is to be reconstituted with 14 mL sterile water for injections (WFI) before
`intravenous injection. Each vial contains 2100 U of rhC1INH (150 U/mL after reconstitution). The
`excipients used in the formulation are sodium citrate, sucrose and citric acid.
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`2.2.2. Active substance
`
`2.2.2.1. Manufacture
`
`Generation of the transgenic herd
`The genomic DNA fragment containing the C1 inhibitor gene and flanking regions was isolated from a
`P1 phage clone. The promoter regions are derived from the casein sequences since the caseins are the
`predominant milk proteins.
`
`Microinjection of DNA into a fertilized oocyte and transfer of the embryo into a foster mother led to the
`generation of a transgenic rabbit (Generation F0). This transgenic male animal was selected as the
`founder, establishing a transgenic line. The founder line was selected on the basis of expression level
`of C1INH in milk, gene copy number, site of integration and number of integration sites. The suitability
`of the selected line was determined by monitoring stability of expression throughout lactation, stability
`of transmission of the transgene, health and fertility of the rabbits Following breeding with a non-
`transgenic female, an F1 male was selected for genetic characterization and sperm collection to
`establish the Master Transgenic Bank (MTB). From the MTB, transgenic bucks were generated and
`genetically characterized. The selected bucks were then used to establish a Manufacturing Working
`Transgenic sperm Bank (MWTB).
`
`The development genetics has been fully discussed with relevant information provided about gene
`construction and identity, copy number, integration site and stability. Similarly, the information
`provided on the establishment, maintenance and pathogen safety of the transgenic line of rabbits is
`satisfactory. A two tier sperm bank has been established and production is limited to transgenic F4
`female New Zealand White rabbits, therefore preventing the possibility of genetic drift.
`
`Manufacture of milk starting material
`The manufacture of the milk starting material includes breeding, maintenance and milking of
`transgenic rabbits.
`
` A
`
` production rabbit colony is a group of rabbits of defined and tested genealogy housed in containment
`behind a biosecurity barrier.
`
`After a general health check, the rabbits are milked using a milking machine. Following collection and
`storage, the milk is skimmed by centrifugation and frozen before transfer to storage facilities. Milk
`from individual rabbits may be pooled prior to skimming.
`
`Besides maintenance of the rabbits as “closed” colonies behind a biosecurity barrier, a comprehensive
`health monitoring program for control of production and sentinel animals are used to control the safety
`of the raw material of the skimmed milk. The applied control procedures are considered acceptable.
`Pooling of thawed skimmed milk is adequately described and ensures a consistent starting material for
`the downstream purification. Control of the process is adequate, including in-process controls for the
`milking of the female rabbits as well as specifications for skimmed milk.
`
`Manufacture of formulated drug substance
`The formulated drug substance is manufactured and routinely controlled in compliance with GMP.
`
`The downstream processing of the milk consists of thawing of milk, pooling of milk bags, fat removal
`by centrifugation and a succession of filtration and chromatography steps as well as viral
`inactivation/removal steps. The drug substance
`is
`formulated using ultra-/diafiltration and
`subsequently filtered and filled in a bag for storage.
`
`Validation
`Three consecutive process validation runs at commercial scale have been performed and extended in
`process control tests have been presented for these batches and compared to data collected from pilot
`scale batches. These data have adequately validated the process and demonstrates process
`comparability to pilot scale manufacturing runs. A summary of all batches which have been used in
`pre-clinical and clinical trials has also been presented and comparability of (pre)-clinical product to
`commercial product has been demonstrated by validation data from the process runs and extended
`characterisation of the product.
`
`
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`Characterisation
`The product has been extensively characterised, and 87% of the amino acid backbone has been
`sequenced. The sites of the 2 disulphide bridges have been identified and 9 of the reported 13 sites of
`glycosylation have been identified. A quantitative assay for isoform analysis has been developed and
`will be implemented as a batch release assay. A quantitative specification will be set after the assay is
`validated and sufficient batch release data has been obtained. Alongside the characterisation data
`presented in the dossier, this extent of sequence identification is considered to be adequate.
`Monosaccharide composition has been demonstrated to be very consistent. Of the sialic acids, only
`NANA has been identified, the potentially immunogenic NGNA has not been found. The N-linked profile
`has been adopted by the Applicant as a drug substance batch release assay, but the O-linked assay
`has not. Instead, the applicant has successfully argued that rates of sialylation and (O-glycosylation)
`site occupancy are the most important parameters to monitor instead of the O-glycosylation profile and
`a site occupancy assay is currently being validated. Sialylation is already a batch release parameter.
`The Applicant has successfully demonstrated that the product has a very low level of host related
`impurities (milk proteins) and that this parameter is well controlled. Clinical assessment has confirmed
`a very low level of patient antibody formation to HRIs.
`
` Specification
`2.2.2.2.
`
`Specifications for the skimmed milk intermediate and the formulated bulk drug substance are generally
`considered adequate to ensure a good level of control. The analytical methods used are considered to
`be state-of-the-art and have been adequately validated. Each batch of active substance is tested for
`appearance, identity, purity, potency, quantity, excipients, general physicochemical properties and
`contaminants.
`
`The rhC1INH activity assay is based on the principle that C1s activity can be measured using a
`commercially available peptide. C1s cleaves the pNA part of the peptide, which absorbs at a
`wavelength of 405 nm. The amount of released pNA is directly proportional to the C1s activity.
`
`Consistency of the protein composition of the skimmed milk starting material is monitored, and a
`qualitative specification for this assay has been set and will be updated with quantitative specifications.
`To ensure blood proteins have not leaked across the blood/mammary barrier, a specific test has also
`been introduced to monitor skimmed milk. A specification for this assay will be set after 20 batches
`have been analysed.
`
`The applicant has committed to monitoring the O-glycan profile for all batches of drug substance, to
`complete validation of the O-glycan site occupancy assay and to introduce a specification for O-linked
`glycosylation.
`
` A
`
` new primary reference standard, derived from a commercial scale batch has been characterised and
`introduced. The procedure to introduce new reference standards has been provided. This reference
`standard is also used for drug product. It should be noted that International Standards for C1INH
`(plasma and concentrate) are being developed. The Applicant has committed to providing traceability
`to an international standard once established.
`
`Batch release data has been provided to demonstrate compliance of commercial product with the
`specifications.
`
` Stability
`2.2.2.3.
`
`Stability studies under real time, accelerated and stress conditions have been performed and the data
`provided support a drug substance shelf life of 3 years at -20°C.
`
`In accordance with EU GMP guidelines 1 , any confirmed out of specification result, or significant
`negative trend, should be reported to the Rapporteur and the EMA.
`
`
`
`
`1 6.32 of Vol. 4 Part I of the Rules Governing Medicinal Products in the European Union
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`2.2.3. Finished Product
`
` Pharmaceutical Development
`2.2.3.1.
`
`Ruconest 2100 U powder for solution for injection is a sterile, non-pyrogenic, preservative-free, white
`to off-white lyophilized powder contained in a single-use type I, colourless sealed glass vial. The
`product is to be reconstituted with 14 mL sterile water for injections (WFI) before intravenous injection.
`The solvent (sterile WFI) for reconstitution is not supplied with the drug product.
`
`Each vial contains 2100 U of conestat alfa (150 U/mL after reconstitution). The excipients used in the
`formulation are sodium citrate, sucrose and citric acid.
`
` A
`
` justification of the formulation components has been provided, along with a description of how the
`formulation was developed. A full description of manufacturing process development has been provided
`which details changes to the process, closure system and fill volume, and relates changes to batch
`numbers and clinical studies.
`
`Initially, liquid formulations were investigated, however it was ultimately decided to have a lyophilised
`presentation as a liquid presentation was considered impractical.
`
`The same composition of drug product has been used throughout clinical development and this is the
`formulation intended for commercial batches.
`
` Adventitious agents
`2.2.3.2.
`
`The rabbit is not considered to be a TSE susceptible species and therefore TSE considerations for the
`rabbit milk are not deemed necessary. Adequate precautions to prevent contamination by TSE from
`alternative sources have been described.
`
`The animals are kept in SPF (specified pathogen free) conditions and are routinely monitored for
`evidence of viral contamination. The manufacturing process has been validated for the inactivation or
`removal of a panel of relevant or model viruses. The two specific virus inactivation/removal steps
`demonstrate excellent capacity for virus depletion with the three chromatography steps also
`contributing to viral safety. A risk assessment has been performed based on the worst case possible
`viral contamination (calculated from the LOD of the in vitro assays and quantity of starting material per
`dose) and validated virus removal capacity of the process.
`
`Overall, and taking all factors into consideration, it is considered that this product should not pose a
`risk to patients through adventitious agents.
`
` Manufacture of the product
`2.2.3.3.
`
`Manufacture of the drug product, including labelling and packaging and batch release, is carried out at
`GMP-qualified sites. Batch release is performed by Pharming Technologies B.V., The Netherlands.
`
`The manufacturing process for the drug product has been described in sufficient detail. Batches of drug
`substance are thawed, pooled, sterile filtered and filled aseptically into vials. The drug product is
`thereafter freeze-dried, capped, inspected, packaged and stored prior to shipment. No other
`components are added in the manufacturing process of the drug product.
`
`The container closure system consists of a type I, colorless glass vial, a siliconized chlorobutyl rubber
`stopper, and a flip-off seal of aluminum and colored plastic.
`
`Critical steps are identified and adequately controlled. The process has been appropriately validated.
`
` Product specification
`2.2.3.4.
`
`The drug product specification is generally relevant and justified, although several limits will be
`updated when 20 batches have been manufactured.
`
`Acceptable batch release data has been presented.
`
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` Stability of the product
`2.2.3.5.
`
`Real-time and accelerated stability studies were performed on 4 batches of finished product. In
`addition, data from one batch stored under stress conditions was provided.
`
`Based on the data presented, a shelf-life for the drug product of 36 months at 25°C is considered
`justified.
`
`The applicant also performed studies on photostability and in-use stability of the reconstituted product.
`
`In accordance with EU GMP guidelines 2 , any confirmed out of specification result, or significant
`negative trend, should be reported to the Rapporteur and the EMEA.
`
` GMO
`2.2.3.6.
`
`The transgenic rabbits are considered to be genetically modified organisms (GMO). The manufacturer
`has been authorised by the authorities to handle transgenic rabbits in a contained environment and the
`rabbit housing areas are classified in accordance with GMO regulations. The product itself is not a GMO.
`
` Discussion on chemical, pharmaceutical and biological aspects
`2.2.3.7.
`
`Information on development, manufacture and control of the drug substance and drug product have
`been presented in a satisfactory manner. The results of tests carried out indicate satisfactory
`consistency and uniformity of important product quality characteristics, and these in turn lead to the
`conclusion that the product should have a satisfactory and uniform performance in the clinic.
`
`Conclusions on the chemical, pharmaceutical and biological aspects
`The quality of this product is considered to be acceptable when used in accordance with the conditions
`defined in the SPC. Physicochemical and biological aspects relevant to the uniform clinical performance
`of the product have been investigated and are controlled in a satisfactory way. Data has been
`presented to give reassurance on viral/TSE safety.
`
`At the time of the CHMP opinion, there were a number of minor unresolved quality issues having no
`impact on the Risk-benefit balance of the product. The applicant gave a Letter of Undertaking and
`committed to resolve these as Follow Up Measures after the opinion, within an agreed timeframe.
`
`2.3. Non-clinical aspects
`
`2.3.1. Introduction
`
`The non-clinical testing program was conducted to establish the safety of rhC1INH for short term use
`(< 7 days) in this chronically debilitating and potentially life-threatening disease. Studies presented
`covered in vitro pharmacology, in vivo safety pharmacology, pharmacokinetics, general toxicology with
`dosing of up to two weeks, teratology in rats and rabbits and local tolerance.
`
`Two different pharmaceutical presentations were developed: a liquid formulation of 25 mg/mL and a
`freeze-dried presentation. Liquid presentations were used in early non-clinical studies. However, from
`formulation studies it became apparent that a lyophilized formulation was preferred for stability
`reasons. Later studies were performed with the lyophilized presentations.
`
`Protocol Assistance from CHMP was obtained on the appropriateness of the proposed duration of
`2 weeks for the repeated dose toxicity studies in rats, to support product safety with regard to the
`intended clinical use of recombinant human C1 inhibitor (acute treatme