Summary Basis of Decision for Oxervate
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Oxervate is located below.
Recent Activity for Oxervate
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Summary Basis of Decision (SBD) for Oxervate
Date SBD issued: 2019-07-24
The following information relates to the new drug submission for Oxervate.
Cenegermin
Drug Identification Number (DIN):
- DIN 02485613 - 0.002% (20 µg/mL), solution, ophthalmic administration
Dompé farmaceutici S.p.A.
New Drug Submission Control Number: 218145
On February 8, 2019, Health Canada issued a Notice of Compliance to Dompé farmaceutici S.p.A. for the drug product Oxervate.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Oxervate is favourable for the treatment of moderate (persistent epithelial defect) or severe (corneal ulcer) neurotrophic keratitis in adults.
1 What was approved?
Oxervate, an ophthalmological drug, was authorized for the treatment of moderate (persistent epithelial defect) or severe (corneal ulcer) neurotrophic keratitis in adults. Cenegermin, the medicinal ingredient in Oxervate, is a recombinant form of human nerve growth factor.
No data were available to Health Canada regarding the efficacy and safety of Oxervate in pediatric patients (younger than 18 years of age). Therefore, Health Canada has not authorized an indication for pediatric use.
Among the subjects who participated in clinical studies of Oxervate, 43.5% were over 65 years of age. No overall differences in safety or effectiveness were observed between elderly and younger adult patients.
Oxervate is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any other non-medicinal ingredient or component of the container.
Oxervate was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Oxervate (0.002% [20 µg/mL] cenegermin) is presented as a solution to be administered as eye drops. In addition to the medicinal ingredient, the solution contains disodium hydrogen phosphate anhydrous, hydrochloric acid, mannitol, nitrogen, polyethylene glycol 6000, L-methionine, sodium dihydrogen phosphate dihydrate, hydroxypropylmethyl cellulose, sodium hydroxide, trehalose dihydrate, and water for injection.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Oxervate Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Oxervate approved?
Health Canada considers that the benefit-risk profile of Oxervate is favourable for the treatment of moderate (persistent epithelial defect) or severe (corneal ulcer) neurotrophic keratitis in adults.
Neurotrophic keratitis is a rare, serious, degenerative disease of the cornea caused by impairment of the trigeminal nerve corneal innervation, which leads to a decrease or absence of corneal sensitivity. Herpetic infections, surgery for trigeminal neuralgia, or surgery for acoustic neuroma are the most common causes of damage to the trigeminal nerve. The impairment or loss of sensory innervation of the cornea affects trophic factors (such as nerve growth factor) responsible for normal tissue maintenance and renewal. The clinical stages of neurotrophic keratitis range from corneal epithelial alterations (stage 1) to persistent epithelial defect (stage 2) and corneal ulcer (stage 3). At stages 2 and 3, the corneal damage is considerable and may lead to corneal infection, perforation, and eventual loss of sight. The estimated prevalence of all stages of neurotrophic keratitis is less than 1.6 per 10,000 persons.
There are currently no drugs approved in Canada for the treatment of neurotrophic keratitis. Depending on the disease stage, degree of damage, and response, treatment may involve artificial tears or autologous serum eye drops, prophylactic topical antibiotics, therapeutic contact lenses, application of cyanoacrylate glue, and/or various surgical interventions such as lid closure or amniotic membrane transplantation.
Cenegermin, the medicinal ingredient in Oxervate, is a recombinant form of human nerve growth factor, an endogenous protein involved in the differentiation and maintenance of neurons. Human nerve growth factor acts through specific high-affinity (i.e., TrkA) and low-affinity (i.e., p75NTR) nerve growth factor receptors. The receptors are expressed in the anterior segment of the eye (cornea, conjunctiva, iris, ciliary body, and lens), by the lacrimal gland, and by posterior segment ocular tissues. The treatment with Oxervate, administered as eye drops, is intended to restore the innervation of the corneal area affected in neurotrophic keratitis patients and to allow restoration of corneal integrity.
Oxervate has been shown to be efficacious in patients with neurotrophic keratitis. The market authorization was based on efficacy and safety data derived from two pivotal, multicentre, randomized, double-masked, vehicle-controlled clinical studies (a Phase I/II study, NGF0212 and a Phase II study, NGF0214). In both studies, 108 patients with moderate to severe neurotrophic keratitis received 20 µg/mL Oxervate administered as one drop six times a day for eight weeks. After the eight-week treatment period, there were significant improvements in Oxervate-treated patients, irrespective of whether improvements were defined as "complete healing" (fluorescein staining in the area of the persistent epithelial defect or corneal ulcer of less than 0.5 mm at greatest diameter) or "completely stain-free" (no residual staining in the area of the defect or persistent staining elsewhere in the cornea). Following eight weeks of double-masked vehicle-controlled treatment, there were 32.7-45.8% more Oxervate-treated patients than vehicle-treated patients who were completely stain-free, and 25.0-37.5% more patients who were completely healed. The magnitude of change in lesion size relative to baseline measurements was also significantly larger for patients treated with Oxervate.
The most common adverse reactions were ocular in nature, and the most common adverse effect was eye pain/discomfort. During the controlled treatment periods of the Phase II studies, adverse events occurred in 64.6% of cenegermin-treated patients and 52.5% of vehicle-treated patients. Serious adverse events occurred in 14.6% of patients in the cenegermin groups and 12.5% of patients in the vehicle groups. Adverse events leading to discontinuation were reported in 18.3% and 12.5% of cenegermin-treated patients and vehicle-treated patients, respectively.
As a growth factor, cenegermin has the potential to affect neoplasms. Therefore, the Warnings and Precautions section of the Oxervate Product Monograph includes a recommendation for using caution and monitoring for cancer progression during and after use of Oxervate in patients with ocular neoplasms.
The commercial formulation of cenegermin (Oxervate), which contains the antioxidant excipient L-methionine, was used in the smaller of the two pivotal studies (study NGF0214). There did not appear to be any differences in safety or efficacy in the two trials between the L-methionine-free and L-methionine-containing formulation of cenegermin. Neither pivotal trial used the delivery system device, which is planned for marketing and will be provided as a separate delivery system weekly kit.
A Risk Management Plan (RMP) for Oxervate was submitted by Dompé farmaceutici S.p.A. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. In addition, to guide first-time users of the novel delivery system, the sponsor has developed a demonstration device kit and educational materials related to the Oxervate vial adapter and pipettes. The sponsor is expected to submit these materials for review by Health Canada prior to the commercial launch of Oxervate in Canada. Of note, the Class II medical device licence required for the pipette was not obtained by the date Oxervate was granted market authorization by Health Canada. However, the device will be made available through the Special Access Programme.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Oxervate Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Oxervate was accepted.
Overall, the therapeutic benefits of Oxervate seen in the pivotal studies are considered to outweigh the potential risks for the target patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Oxervate Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Oxervate?
The drug submission for Oxervate was reviewed under the Priority Review Policy. The sponsor has submitted sufficient evidence demonstrating that Oxervate provides an effective treatment for moderate or severe neurotrophic keratitis, a serious, severely debilitating disease for which no drug is presently marketed in Canada.
Submission Milestones: Oxervate
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2018-01-26 |
| Request for priority status | |
| Filed: | 2018-05-08 |
| Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics: | 2018-05-15 |
| Submission filed: | 2018-07-16 |
| Screening | |
| Screening Acceptance Letter issued: | 2018-08-14 |
| Review | |
| Quality Evaluation complete: | 2019-01-24 |
| Clinical/Medical Evaluation complete: | 2019-02-06 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2019-02-08 |
| Review of Risk Management Plan complete: | 2018-12-24 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2019-02-08 |
The Canadian regulatory decision on the quality, non-clinical and clinical reviews of Oxervate was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
As part of the marketing authorization for Oxervate, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) submitting to Health Canada:
- Periodic Benefit-Risk Evaluation Reports, every six months for three years after marketing or as requested by Health Canada thereafter
- a demonstration device kit and any educational materials related to the Oxervate vial adapter and pipettes for review by Health Canada prior to marketing in Canada
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
The medicinal ingredient in Oxervate is cenegermin, a recombinant form of human nerve growth factor. Nerve growth factor is an endogenous protein involved in the differentiation and maintenance of neurons, and acts through specific high-affinity (i.e., TrkA) and low-affinity (i.e., p75NTR) nerve growth factor receptors. These receptors are expressed in the anterior segment of the eye (cornea, conjunctiva, iris, ciliary body, and lens), by the lacrimal gland, and by posterior segment ocular tissues. The treatment with cenegermin, administered as eye drops, is intended to restore the innervation of the corneal area affected in neurotrophic keratitis patients and to allow restoration of corneal integrity.
Pharmacodynamic studies have not been conducted in humans with cenegermin (with or without L-methionine, an excipient present in the commercial formulation of cenegermin). This was considered acceptable, as the mechanism of action of cenegermin was sufficiently assessed in non-clinical studies.
No pharmacokinetic studies have been conducted with the commercial formulation of cenegermin. The pharmacokinetic profile of cenegermin without L-methionine was assessed in a Phase I study, NGF0112, and in the pivotal Phase I/II study, NGF0212 (described in the Clinical Efficacy section). In study NGF0112, healthy volunteers were administered cenegermin at concentrations up to 180 µg/mL, one eye drop three times a day for five days. In study NGF0212, patients with moderate to severe neurotrophic keratitis were treated with 10 µg/mL or 20 µg/mL, one drop six times a day for eight weeks. In both studies, systemic cenegermin levels were below the detection limit in the majority of the subjects, both pre-dose and post-dose. In the few subjects with detectable systemic cenegermin levels post-dose, the levels observed were similar to those obtained at baseline.
The clinical pharmacology data support the use of Oxervate for the recommended indication.
For further details, please refer to the Oxervate Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Oxervate (cenegermin) for the treatment of neurotrophic keratitis was evaluated in two pivotal, multicentre, randomized, double-masked, vehicle-controlled clinical studies (a Phase I/II study, NGF0212 and a Phase II study, NGF0214).
The pivotal clinical studies were conducted in adult patients with stage 2 (moderate, persistent epithelial defect) or stage 3 (severe, corneal ulcer) neurotrophic keratitis refractory to non-surgical treatments. There were 177 patients treated with two different doses of cenegermin (10 µg/mL and 20 µg/mL) in two different formulations (with or without L-methionine, an excipient present in the to-be-marketed formulation). Thirty-six patients received the L-methionine-containing formulation of 20 µg/mL cenegermin administered according to the recommended dosing regimen, one drop six times per day in the affected eye(s) for eight weeks. The mean age of the population studied was 61 (range of 18 to 95 years) in study NGF0212 and 65 (range from 33 to 94 years) in study NGF0214. In both studies, there were 60% female patients. In study NGF0212, only patients with unilateral disease could be enrolled, while in study NGF0214 enrollment was allowed also for patients with bilateral disease. Following the controlled treatment period of eight weeks, patients entered a follow-up period of 48 or 56 weeks (study NGF0212), and 24 or 32 weeks (study NGF0214). Neither study used the to-be-marketed delivery device for administration of drops (see Why was Oxervate approved?).
The studies initially defined the primary efficacy endpoint, complete healing, as the percentage of patients with a lesion size of <0.5 mm on corneal fluorescein staining in the area of the persistent epithelial defect or corneal ulcer. Upon request by the United States Food and Drug Administration (during the regulatory approval process of Oxervate in the United States), post hoc analyses were conducted using a revised (completely stain-free) primary efficacy endpoint. This was defined as percentage of patients experiencing no corneal fluorescein staining in the area of the persistent epithelial defect or corneal ulcer and no persistent staining elsewhere in the cornea (i.e., 0 mm lesion size and no residual staining). Despite being post hoc, the analyses have been conducted with adequate statistical rigor and refer to a more meaningful clinical endpoint than the initially defined endpoint, complete healing. Accordingly, the Oxervate Product Monograph presents first the results for the revised primary efficacy endpoint.
Due to high rates of patient dropout and non-compliance, a conservative non-responder imputation was used to assess efficacy. Thus, patients who withdrew or did not have endpoint data for another reason were imputed to be not completely healed or not completely stain-free. Using this "worst-case" approach, there were similar proportions of patients treated with 20 µg/mL cenegermin at Week 8 who were completely stain-free (65.4% and 58.3%) or completely healed (67.3% and 65.2%) in study NGF0212 and study NGF0214, respectively. In the vehicle groups, the proportions of patients with completely stain-free or completely healed lesions ranged from 12.5% to 42.3%. The relatively high responder rate seen in some of the vehicle groups is attributable to consistent application of eye drops (even though they contained no active ingredient), since maintaining moisture on the surface of the eye is beneficial to corneal epithelial health and integrity. The mean percent change in lesion size compared to baseline measurements was significantly greater for the cenegermin groups versus vehicle groups (the mean difference in lesion size change between cenegermin- and vehicle-treated patients was -52.8% in study NGF0212 and -72.9% in study NGF0214).
Of note, in study NGF0212, where two dose levels of cenegermin (10 µg/mL and 20 µg/mL) were compared to vehicle drops, there was no significant difference favouring 20 µg/mL over 10 µg/mL. The sponsor chose the 20 µg/mL dose level for use in the second pivotal trial (NGF0214) and for commercial use, on the basis of modest numerical (but not statistically significant) differences between the two cenegermin dose levels.
While the primary endpoints were met for both studies, there were inconsistent results for several of the secondary endpoints, such as mean change from baseline in best corrected distance visual acuity, investigator global evaluation of efficacy, and improvement in corneal sensitivity. In most cases, however, a numerical difference favoured the cenegermin groups. Notably, the studies enrolled small numbers of patients and had a relatively high proportion of withdrawals/discontinuations.
Indication
The New Drug Submission for Oxervate was filed by the sponsor with the following indication, which Health Canada subsequently approved:
- Oxervate (cenegermin) ophthalmic solution is indicated for the treatment of moderate (persistent epithelial defect) or severe (corneal ulcer) neurotrophic keratitis in adults.
For more information, refer to the Oxervate Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of cenegermin, the medicinal ingredient in Oxervate, was evaluated in 530 adults who were exposed to cenegermin eye drops (at different formulations, dosages and treatment periods) across clinical trials conducted in healthy volunteers and patients with different conditions (i.e., neurotrophic keratitis and other ocular pathologies). Among the 530 adults, there were 108 patients with moderate to severe neurotrophic keratitis who received 20 µg/mL cenegermin administered as one drop six times a day, for eight weeks, in two double-blinded vehicle-controlled clinical studies (a Phase I/II study, NGF0212, and a Phase II study, NGF0214, described in the Clinical Efficacy section). Study NGF0214 used the commercial formulation of cenegermin, which contains the antioxidant L-methionine.
The safety profile of cenegermin was similar across all indications for which cenegermin was studied, with the most common adverse reactions being ocular in nature. The most common ocular adverse reaction in patients with neurotrophic keratitis was eye pain or ocular discomfort.
During the controlled treatment periods of the Phase II studies, adverse events occurred in 64.6% of cenegermin-treated patients and 52.5% of vehicle-treated patients. Serious adverse events occurred in 14.6% of patients in the cenegermin groups and 12.5% of patients in the vehicle groups. Adverse events leading to discontinuation were reported in 18.3% and 12.5% of cenegermintreated patients and vehicle-treated patients, respectively.
There were six deaths in the extension phases of the clinical trials in patients with neurotrophic keratitis who had received cenegermin treatment. All deaths were considered unrelated to treatment, as they occurred weeks or months after the end of the eight-week cenegermin treatment cycle and reflected underlying pathologies of the older patient population.
Appropriate warnings and precautions are in place in the approved Oxervate Product Monograph to address the identified safety concerns.
For more information, refer to the Oxervate Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical data support the use of Oxervate for the specified indication.
The pharmacology studies demonstrated that cenegermin, the medicinal ingredient in Oxervate, was able to bind to the high-affinity nerve growth factor receptors, TrkA, and lead to proliferation of neuronal or corneal epithelial cells in rat and rabbit models.
The toxicology studies of cenegermin included single- and repeat-dose studies conducted in healthy rats and rabbits, using the topical ocular route (eye drops) or systemic (subcutaneous) route of administration.
In the topical repeat-dose studies, eye drops of cenegermin were administered for 26 weeks in rats and two months in rabbits. There were no adverse ocular toxicities noted at doses corresponding to 3.8- and 23-fold the maximum recommended human ophthalmic dose (MRHOD) in rats and rabbits, respectively, as calculated by direct comparison of the animal dose to the human dose.
Systemic toxicity was evaluated in studies using subcutaneous and topical administration of cenegermin. Of note, systemic drug exposure following topical administration was higher than expected in rats due to the passage of the drug through the nasolacrimal and nasopharyngeal ducts into the oral cavity. The main toxicological findings consisted of adverse ovarian effects (i.e., increased ovary weights, cell proliferation, hemorrhagic cysts, and corpora lutea), which were observed in both rats and rabbits following topical ocular administration and in rabbits following subcutaneous administration. A drug-related effect could not be ruled out for the ovarian findings.
Immune reactions (including swelling and erythema of the head, ears, tail, and/or legs) were observed in animals across multiple studies, likely due to the exposure to a heterologous protein. Consequently, the effect is unlikely to be relevant to humans.
In reproductive and developmental toxicology studies, cenegermin (administered subcutaneously) was associated with an increase in the rate of postimplantation loss in both rats and rabbits. In rats, an increase in the incidence of fetal malformations (i.e., hydrocephaly and ureter abnormalities) was observed. In rabbits, there was a small increase in the incidence of fetal cardiac malformations, i.e., ventricular and atrial septal defects, enlarged heart, and aortic arch dilation. The human systemic exposure to cenegermin following ocular administration at the MRHOD is expected to be low. Therefore, the clinical relevance of the animal developmental toxicology findings (observed following subcutaneous administration) is unclear.
Carcinogenicity and genotoxicity studies were not conducted for cenegermin. This is in line with the International Council for Harmonization guidelines "Preclinical safety evaluation of biotechnology-derived pharmaceuticals S6(R1)" and the carcinogenicity risk assessment provided by the sponsor. As a growth factor, cenegermin has the potential to affect neoplasms. Accordingly, the Warnings and Precautions section of the Oxervate Product Monograph includes a recommendation for using caution and monitoring for cancer progression during and after use of Oxervate in patients with ocular neoplasms.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Oxervate Product Monograph. In view of the intended use of Oxervate, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
Appropriate warnings and precautionary measures are in place in the Oxervate Product Monograph to address the identified safety concerns.
For more information, refer to the Oxervate Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Characterization of the Drug Substance
The medicinal ingredient in Oxervate, cenegermin, is a recombinant human nerve growth factor produced in Escherichia coli as a pro-protein. The pro-protein is cleaved during the production process to generate a mature protein, which has an amino acid sequence that is identical to naturally secreted human nerve growth factor.
Detailed characterization studies were performed to provide assurance that cenegermin consistently exhibits the desired characteristic structure and biological activity.
Results from process validation studies indicate that the manufacturing processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The drug substance is manufactured from Escherichia coli using recombinant deoxyribonucleic acid (DNA) technology. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested in accordance with the International Council for Harmonisation (ICH) guidelines.
The manufacturing process of the drug substance is a multistep process. The upstream process includes inoculum preparation, seed fermentation, production fermentation, biomass recovery, cell disruption by high pressure homogenization, and recovery of inclusion bodies (i.e., an intermediate containing pro-nerve growth factor [proNGF] inclusion bodies). The intermediate may either be stored at -70±10°C until downstream processing or immediately processed without storage. Each batch of the intermediate must meet defined release specifications. The purification process involves solubilization, refolding of the proNGF to the native conformation and clarification by depth filtration, followed by a trypsin hydrolysis step to cleave the pro-sequence. Subsequently, the cleaved protein is purified through chromatography steps, filtered, and stored at -20±5°C for up to 48 months.
The sponsor has demonstrated that the proposed drug substance manufacturing site is capable of consistently manufacturing cenegermin of acceptable quality. The materials used in the manufacturing of the drug substance are considered suitable and/or meet standards appropriate for their intended use.
The manufacturing of the drug product involves thawing of the drug substance, pooling, formulating, filtering, and filling into siliconized 2 mL glass vials. The sponsor has demonstrated that the proposed drug product manufacturing facility is capable of consistently manufacturing drug product of acceptable quality.
The sponsor has developed a control strategy to ensure the quality of the drug substance and drug product, and has demonstrated that the testing laboratories are capable of performing the required release and stability testing.
Oxervate drug product is a sterile preservative-free ophthalmic solution containing 20 µg/mL of cenegermin. The proposed commercial drug product is packaged in multi-dose siliconized type I glass vials closed with a rubber stopper and an aluminium seal with a polypropylene flip-off. Each vial contains 1.0 mL of solution. Seven multi-dose vials are packaged in a weekly carton and a separate delivery system weekly kit includes specific vial adapters and disposable pipettes.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of cenegermin with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with the International Council for Harmonisation (ICH) guidelines.
As a Schedule D (biologic) drug, Oxervate is subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed shelf life of 24 months at -20±5ºC and in-use storage conditions for the drug product of up to 12 hours at 25°C and up to 14 days at 2-8°C are considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
An on-site evaluation of the drug substance manufacturing facility was recommended based on a risk assessment score. However, no production was scheduled during the submission review cycle. In addition, as the drug substance manufacturing process is not based on a manufacturing platform, it was not possible to observe the production of a surrogate product. Consequently, an on-site evaluation of the drug substance manufacturing facility could not be performed in support of this quality review. Sufficient information was obtained from the manufacturer to ensure that the quality of the product supported the marketing authorization. An on-site evaluation of the drug substance manufacturing facility will be conducted at the next opportunity.
An on-site evaluation of the facility involved in the manufacture of the drug product was not recommended as determined by a risk assessment score. The facility was evaluated by Health Canada in 2009 and obtained a satisfactory rating.
Adventitious Agents Safety Evaluation
The cenegermin manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control.
No raw materials of animal or human origin are used in the manufacture of the drug substance and drug product. In addition, none of the excipients used in the drug product formulation are derived from materials of human or animal origin. Given that the recombinant protein is produced in a bacterial expression host, an assessment of bacteriophage contamination has been performed to confirm that the parental strain, the master cell bank, and the working cell bank are free of prophage and phage contamination. Bioburden and endotoxin testing are integrated in the control strategy and meet relevant guidelines and requirements.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| OXERVATE | 02485613 | DOMPÉ FARMACEUTICI S.P.A. | CENEGERMIN 0.002 % |