Summary Basis of Decision for Ngenla
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 Ngenla is located below.
Recent Activity for Ngenla
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 Ngenla
Date SBD issued: 2022-01-31
The following information relates to the new drug submission for Ngenla.
Somatrogon
Drug Identification Number (DIN):
- DIN 02521679 - 20 mg/mL somatrogon, solution, subcutaneous administration
- DIN 02521687 - 50 mg/mL somatrogon, solution, subcutaneous administration
Pfizer Canada ULC
New Drug Submission Control Number: 246729
On October 26, 2021, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for the drug product Ngenla. 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 Ngenla is favourable for the long‑term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone (growth hormone deficiency).
1 What was approved?
Ngenla, a human growth hormone analogue, was authorized for the long‑term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone (growth hormone deficiency).
The efficacy and safety of Ngenla in pediatric patients 3 to 11 years of age with growth failure due to growth hormone deficiency have been established in clinical trials. The efficacy and safety of Ngenla have not been established in patients under 3 years of age. Data on the efficacy and safety of Ngenla in patients 12 to under 18 years of age are limited. Pediatric patients with growth failure due to acquired growth hormone deficiency caused by a malignancy were not studied in clinical trials.
Ngenla is not indicated for use in adults (≥18 years of age). No clinical safety or efficacy data are available to Health Canada, therefore, Health Canada has not authorized an indication for use in geriatric patients (≥65 years of age).
Ngenla (20 mg somatrogon/mL and 50 mg somatrogon/mL) is presented as a solution in a prefilled pen. In addition to the medicinal ingredient, the solution contains citric acid monohydrate, L‑histidine, m‑cresol, poloxamer 188, sodium chloride, trisodium citrate dihydrate, and water for injection.
The use of Ngenla is contraindicated in patients with closed/fused epiphyses; active malignancy; or acute critical illness due to complications following open heart surgery, abdominal surgery, multiple accidental trauma, or acute respiratory failure. Additionally, Ngenla is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Ngenla Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
2 Why was Ngenla approved?
Health Canada considers that the benefit‑risk profile of Ngenla is favourable for the long‑term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone (growth hormone deficiency).
Growth hormone deficiency is a rare condition that occurs in children when the pituitary does not produce sufficient quantities of growth hormone to ensure normal growth. Human growth hormone is a polypeptide hormone that stimulates growth and cell reproduction via its action at growth hormone receptors in target cells. Many of the effects of human growth hormone are mediated by insulin-like growth factor‑1 (IGF‑1); both are important in the regulation of metabolism and for the promotion of linear growth in children. The underlying causes of growth hormone deficiency can be congenital (resulting from structural or genetic abnormalities) or a result of acquired damage to the hypothalamus and/or pituitary from disease, trauma, chemotherapy, or malignancy. In some patients, the exact underlying cause cannot be determined. Patients with growth hormone deficiency, regardless of etiology, can develop growth failure. Growth failure is defined as a standing height more than two standard deviations below the population mean for their age and sex. Without treatment, these children can remain very short into adolescence and adulthood and are at risk of serious metabolic and quality of life sequelae, for example, reduced lean muscle mass and strength, osteoporosis, abnormal lipid profile/increased risk of cardiovascular disease, and mental illness due to stigma.
Growth hormone deficiency is the most common endocrine‑related cause of short stature, but it is rare. No published Canadian prevalence data are available; however, based on international sources, the prevalence in Canada is estimated to be approximately 1,800 patients. In Canada, the current standard of care treatment for children affected by growth failure due to growth hormone deficiency consists of once‑daily subcutaneous injections of somatropin, a recombinant human growth hormone that effectively replaces endogenous growth hormone.
Ngenla (somatrogon injection) is a recombinant human growth hormone molecule that has been modified to include one copy of the C‑terminal peptide of the beta chain of human chorionic gonadotropin at its N‑terminus and two copies of C‑terminal peptide (in tandem) at its C‑terminus. These modifications extend its half‑life relative to endogenous and recombinant human growth hormone/somatropin, permitting weekly subcutaneous dosing, compared to daily subcutaneous dosing.
The efficacy and safety of Ngenla for the treatment of pediatric patients with growth hormone deficiency were evaluated in two randomized, open‑label, active‑controlled clinical studies, CP‑4‑006 (a Phase III study) and CP‑4‑004 (a supportive Phase II study). Both studies directly compared the efficacy of once‑weekly subcutaneous administration of Ngenla with once‑daily subcutaneous administration of Genotropin (somatropin; the current standard of care).
In study CP‑4‑006, patients were treated with 0.66 mg/kg body weight of Ngenla once weekly by subcutaneous administration or 0.034 mg/kg body weight of Genotropin once daily by subcutaneous administration. After 12 months of treatment, Ngenla‑treated patients had a mean height velocity of 10.10 centimeters per year and Genotropin‑treated patients had a mean height velocity of 9.78 centimeters per year. The mean increase in height velocity in Ngenla‑treated patients was non-inferior to that of Genotropin‑treated patients and the efficacy results were clinically meaningful. The results of the key secondary efficacy endpoints (height standard deviation score at 12 months and change in height standard deviation score from baseline at 12 months) were not meaningfully different between the two treatment groups and supported the primary efficacy endpoint results.
In study CP‑4‑004, after 12 months of treatment, annualized height velocity was 11.4 cm per year in patients treated with 0.66 mg/kg body weight of Ngenla once weekly by subcutaneous administration and 12.5 cm per year in patients treated with 0.034 mg/kg body weight of Genotropin once daily by subcutaneous administration. Overall, the efficacy results from study CP‑4‑004 were generally similar to, and therefore supportive of, those from study CP‑4‑006.
The risks associated with Ngenla treatment were injection site reactions, including injection site pain, erythema, pruritus, swelling, induration, bruising, haemorrhage, and warmth. These reactions were not associated with hypersensitivity or anaphylactic reactions. The increased frequency observed in Ngenla‑treated patients compared to Genotropin‑treated patients has been appropriately communicated in the Ngenla Product Monograph, including instructions on what to do if these reactions occur.
Glucose metabolism impairment, thyroid function impairment, cortisol changes, neoplasias, intracranial hemorrhage, intracranial aneurysm, intracranial hypertension, pancreatitis, and epiphyseal disorders are class-based important potential identified risks of somatropin‑containing products and were considered important for Ngenla due to their shared mechanism of action. No clinically meaningful difference in incidence of these events were reported between Ngenla‑ and Genotropin‑treated patients. Notably, no patients in either group reported elevated pancreatic enzymes or diagnosis of acute or chronic pancreatitis, intracranial hypertension, malignant neoplasia, intracranial hemorrhage, intracranial aneurysm, or slipped capital femoral epiphysis.
A Risk Management Plan (RMP) for Ngenla was submitted by Pfizer Canada ULC 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.
The submitted inner and outer labels and Patient Medication Information section of the Ngenla Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements. The finalized package insert will be provided within 20 days from the issuance of the Notice of Compliance.
The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Ngenla was accepted.
Overall, Ngenla has been shown to have a favourable benefit‑risk profile based on non‑clinical and clinical studies.
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 Ngenla?
The New Drug Submission (NDS) for Ngenla was reviewed as part of the New Active Substance Work Sharing Initiative (NASWSI), a work‑sharing initiative between Canada, Australia, Singapore, Switzerland, and the United Kingdom (the Access Consortium). This partnership aims to promote collaboration between regulatory agencies, optimize the use of resources, reduce duplication, and enhance each agency's ability to ensure consumers have timely access to safe, effective, and high‑quality therapeutic products.
Health Canada completed the review of the clinical component of the NDS for Ngenla, while Australia's Therapeutic Goods Administration completed the review of the non‑clinical and quality components. The review of the submission was collaborative, with each regulatory agency sharing the outcome of its review with the others. However, each agency made its regulatory decision independently.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Ngenla
| Submission Milestone | Date |
|---|---|
| New Drug Submission filed | 2020-11-24 |
| Screening | |
| Screening Acceptance Letter issued | 2020-12-31 |
| Review | |
| Review of Risk Management Plan completed | 2021-10-05 |
| Quality evaluation completed | 2021-10-11 |
| Non-clinical evaluation completed | 2021-10-22 |
| Clinical/medical evaluation completed | 2021-10-22 |
| Labelling review completed | 2021-10-22 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2021-10-26 |
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
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
As described above, the clinical review of the New Drug Submission for Ngenla was completed by Health Canada as part of the New Active Substance Work Sharing Initiative with Australia's Therapeutic Goods Administration. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.
Clinical Pharmacology
Somatrogon, the medicinal ingredient in Ngenla, binds to the growth hormone receptor and initiates a signal transduction cascade culminating in changes in growth and metabolism. Consistent with growth hormone signaling, somatrogon binding leads to activation of the signal transducer and activator of transcription 5b (i.e., STAT5b) signaling pathway and induces cell proliferation in vitro. Somatrogon has also been shown to increase the serum concentration of insulin‑like growth factor‑1 (IGF‑1).
The clinical pharmacology evaluation of somatrogon included a number of pharmacodynamic and pharmacokinetic studies. In clinical studies and pharmacologic modelling reports, weight‑based dosing with 0.66 mg/kg of somatrogon once per week was shown to be appropriate for attaining the target IGF‑1 standard deviation score (SDS) of ±2 in pediatric patients. There were no covariates, other than weight, that were shown to have a meaningful or consistent effect on somatrogon pharmacodynamics or pharmacokinetics. Somatrogon may be a weak inducer of cytochrome P450 3A4. The presence of the human chorionic gonadotropin-derived C‑terminal peptide domain on somatrogon was shown not to interfere with standard pregnancy testing. The IGF‑1 SDS at Day 4 was shown to be a good indicator of the average IGF‑1 SDS over the course of the weekly dosing interval. The clinical pharmacology program had some limitations, including very little information in adolescent patients, since the oldest patients were 12 years old at study entry and only entered adolescence in the open‑label extensions of the studies.
Overall, the clinical pharmacology data support the use of Ngenla for the recommended indication.
For further details, please refer to the Ngenla Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Ngenla for the treatment of pediatric patients with growth hormone deficiency was evaluated in two clinical studies, CP‑4‑004 and CP‑4‑006.
Study CP‑4‑006 was an open‑label, randomized, multicentre safety and efficacy Phase III study that enrolled 224 pre-pubertal pediatric patients aged 3 to 11 years with growth failure due to growth hormone deficiency and who were naive to growth hormone therapy. The objective of the study was to determine whether treatment with Ngenla was non‑inferior to treatment with Genotropin (somatropin) for the primary efficacy endpoint of height velocity (cm/year) at 12 months. Patients were randomized and treated for one year with 0.66 mg/kg body weight of Ngenla once weekly by subcutaneous administration (number of patients [n] = 109) or 0.034 mg/kg body weight of Genotropin once daily by subcutaneous administration (n = 115). Overall, 72% of patients were male, 75% were white, 20% were Asian, 1% were Black or African American, and 11% were Hispanic or Latino. At baseline, mean (min, max) age was 7.72 (3.01, 11.96) years, 40% of patients were aged 3 to 6 years, and 60% were aged 7 years and older. Mean (min, max) height was 110 (75, 144) cm and mean height SDS (min, max) was ‑2.86 (‑9.96, ‑0.47).
After 12 months of treatment, the mean height velocity was 10.10 cm/year in Ngenla‑treated patients and 9.78 cm/year in Genotropin‑treated patients. The mean increase in height velocity in Ngenla‑treated patients met the pre‑specified non‑inferiority margin of ‑1.8 cm/year and was considered clinically meaningful as compared to historical information on untreated children with growth hormone deficiency. These primary efficacy endpoint results were supported by the key secondary efficacy endpoints (height SDS at 12 months and change in height SDS from baseline at 12 months) which were not meaningfully different between the two treatment groups.
Study CP‑4‑004 was an open‑label, randomized, safety and dose‑finding Phase II study that enrolled 53 pre‑pubertal pediatric patients aged 3 to 11 years with growth failure due to growth hormone deficiency and who were naive to growth hormone therapy. Patients were randomized to be treated with either 0.25 mg/kg body weight (n = 13), 0.48 mg/kg body weight (n = 15), or 0.66 mg/kg body weight (n = 14) of Ngenla once weekly by subcutaneous administration or 0.034 mg/kg body weight of Genotropin (somatropin; n = 11) once daily by subcutaneous administration. Overall, 60% of patients were male, 96% were white, 0% were Asian, 2% were Black or African American, and 2% were ‘Other’. At baseline, mean (min, max) age was 6.4 (3.0, 11.2) years, 64.2% of patients were aged 3 to 6 years, and 35.8% were aged 7 years and older. Mean (min, max) height was 101.5 (81.5, 127.5) cm and mean height SDS (min, max) was ‑4.0 (‑7.5, ‑2.3). After 12 months, annualized height velocity was 11.4 cm/year in Ngenla‑treated patients (0.66 mg/kg body weight) and 12.5 cm/year in Genotropin‑treated patients. In the open‑label extensions of study CP‑4‑004, continued increases in height were observed in 35 of the 53 Ngenla‑treated patients who had completed the main study and were treated with 0.66 mg/kg body weight per week for at least five years.
In studies CP‑4‑004 and CP‑4‑006, treatment compliance was not meaningfully different between the Ngenla‑ and Genotropin‑treated patients, and the Quality of Life in Short Stature Youth survey results were not sufficiently robust to substantially support the demonstration of improved quality of life in patients treated with Ngenla compared to Genotropin. More Ngenla‑treated patients had injection site reactions than those treated with Genotropin, despite the lower number of total injections (see Clinical Safety section). These results notwithstanding, the use of once‑weekly Ngenla, particularly in this pediatric population requiring chronic treatment for growth hormone deficiency, may provide some degree of incremental quality of life/convenience‑related benefit over use of daily somatropin products solely due to the decreased number of injections required. This decreased injection burden provides an additional marginal beneficial effect for Ngenla that supplements its growth‑related benefits.
Indication
The New Drug Submission for Ngenla was filed by the sponsor with the following indication:
- The long‑term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone.
Health Canada approved the following indication:
- The long‑term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone (growth hormone deficiency).
For more information, refer to the Ngenla Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety profile of Ngenla was derived from studies CP‑4‑006 and CP‑4‑004, described in the Clinical Efficacy section, and comprised a combined total exposure to Ngenla of 476.8 patient‑years.
In study CP‑4‑006, the most common adverse reactions in pediatric patients with GHD treated with Ngenla were injection site reactions (43.1%), headache (16.5%), and pyrexia (16.5%) compared to pediatric patients with GHD receiving somatropin (25.2%, 21.7%, and 13.9%, respectively). Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti‑drug antibodies [ADAs]). Of the 109 patients in the Ngenla group, 84 patients tested positive for ADAs at any time during the 12‑month treatment period; however, ADA status did not appear to be associated with a difference in safety profile with respect to adverse events. The longer‑term safety and efficacy of Ngenla will be monitored as part of routine and non‑routine pharmacovigilance, and is included in the Risk Management Plan for Ngenla as an important potential risk.
Glucose metabolism impairment, thyroid function impairment, cortisol changes, neoplasias, intracranial hemorrhage, intracranial aneurysm, intracranial hypertension, pancreatitis, and epiphyseal disorders are class-based important potential identified risks of somatropin‑containing products and were considered important for Ngenla due to their shared mechanism of action. No clinically meaningful difference in incidence of these events were reported between Ngenla‑ and Genotropin‑treated patients. Notably, no patients in either group reported elevated pancreatic enzymes or diagnosis of acute or chronic pancreatitis, intracranial hypertension, malignant neoplasia, intracranial hemorrhage, intracranial aneurysm, or slipped capital femoral epiphysis.
In study CP‑4‑006, 12 Ngenla-treated patients (versus 0 in the Genotropin‑treated group) required dose reductions due to IGF‑1 levels that exceeded two standard deviation scores above normal values (SDS>+2) for the patients’ sex and age. Given that in the clinical development program, dosing was reduced if a patient had an IGF‑1 SDS>+2 at two consecutive times, there are no clinical safety data for patients with a persistently elevated IGF‑1 SDS>+2. Although no IGF‑1-related adverse events were reported in patients with consecutive elevations in IGF‑1, this does not exclude the potential for a safety issue associated with chronic elevations of IGF‑1. As is included for somatropin‑containing products, guidance for dosing adjustment based on clinical response and serum IGF‑1 levels, as well as guidance for timelines on IGF‑1 sampling, has been included in the Ngenla Product Monograph.
Ngenla’s weekly dosing regimen could be confused with existing treatment options that are administered daily (i.e., somatropin) and may result in accidental overdose. Doses of Ngenla higher than 0.66 mg/kg body weight per week have not been studied, hence there is no clinical experience of overdose with Ngenla. As such, the information on overdose that has been proposed in the Ngenla Product Monograph is based on data from growth hormone products with a shorter half‑life. This important potential risk has been appropriately mitigated through additional labelling measures in the Ngenla Product Monograph and through post‑market pharmacovigilance.
Additionally, other important potential risks identified in the Risk Management Plan for Ngenla include diabetes mellitus type 2 and benign and malignant neoplasia.
Overall, the safety profile of once-weekly Ngenla was generally consistent with that of once‑daily Genotropin, with the exception of increased risk of injection site reactions, which will be managed post-market through additional labelling and post‑market pharmacovigilance.
Appropriate warnings and precautions are in place in the approved Ngenla Product Monograph to address the identified safety concerns. For more information, refer to the Ngenla Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
As described above, the New Drug Submission (NDS) for Ngenla was reviewed as part of the New Active Substance Work Sharing Initiative. Australia's Therapeutic Goods Administration completed the review of the non‑clinical component of the NDS for Ngenla. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.
Key studies in the non‑clinical package for Ngenla consisted of primary pharmacodynamic, repeat‑dose toxicity, and reproductive and developmental toxicity studies.
In in vitro primary pharmacodynamic studies, somatrogon, the medicinal ingredient in Ngenla, was shown to bind to the human growth hormone receptor and to induce functional activity in relevant cell‑based assays.
All in vivo toxicology studies were conducted in pharmacologically relevant species and using the subcutaneous route of administration. In adult rats, somatrogon administration in a 4‑week repeat‑dose toxicity study resulted in findings consistent with those observed with somatropin (e.g., increased body weight, body weight gain, food consumption; mammary gland feminization in males, and mammary gland lobular hyperplasia in females). Similar findings or other adverse effects were not observed in juvenile rhesus monkeys in the pivotal 26‑week repeat‑dose toxicity study. The no‑observed-adverse-effect level (NOAEL) in this study was 30 mg/kg once every 5 days, which was the highest dose tested and equivalent to 193 times the human exposure based on area under the serum drug concentration‑time curve (AUC).
There were also no adverse effects in pivotal reproductive and developmental toxicity studies conducted in rats, which consisted of a male and female fertility and early embryonic development study, an embryo‑fetal development study, and a pre‑ and postnatal development study. The NOAEL in these studies was 30 mg/kg once every 2 days, which was the highest dose tested (equivalent to 51 times the human exposure based on AUC in the embryo‑fetal development study).
Carcinogenicity and genotoxicity studies were not conducted, which was considered acceptable and in accordance with International Council for Harmonisation guidelines.
Overall, the results of the non‑clinical studies as well as the potential risks to humans have been included in the Ngenla Product Monograph. In view of the intended use of Ngenla, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Ngenla Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
As described above, the New Drug Submission (NDS) for Ngenla was reviewed as part of the New Active Substance Work Sharing Initiative. Australia's Therapeutic Goods Administration completed the review of the quality component of the NDS for Ngenla. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.
Characterization of the Drug Substance
Somatrogon, the medicinal ingredient in Ngenla, is a glycoprotein produced in Chinese hamster ovary cells by recombinant deoxyribonucleic acid (DNA) technology. It is a C‑terminal peptide (CTP)‑modified recombinant human growth hormone comprised of the amino acid sequence of human growth hormone with one copy of the CTP from the beta chain of human chorionic gonadotropin at the N‑terminus and two copies of CTP (in tandem) at the C‑terminus. Somatrogon binds to the growth hormone receptor and initiates a signal transduction cascade culminating in changes in growth and metabolism. Consistent with growth hormone signaling, somatrogon binding leads to activation of the signal transducer and activator of transcription 5b (i.e., STAT5b) signaling pathway and increases the serum concentration of insulin‑like growth factor‑1 (IGF‑1). As a result, growth hormone and IGF‑1 stimulate metabolic changes and linear growth, and enhance growth velocity in pediatric patients with growth hormone deficiency.
Detailed characterization studies were performed to provide assurance that somatrogon consistently exhibits the desired characteristic structure and biological activity.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The drug substance is manufactured from Chinese hamster ovary cells using recombinant DNA technology. The manufacturing process of the drug substance begins with the thawing of somatrogon working cell vials, followed by expansion, concentration, diafiltration and filtration, virus inactivation, and purification steps.
The sponsor has demonstrated that the drug substance manufacturing facility is capable of consistently manufacturing somatrogon of acceptable quality. Appropriate in‑process controls have been implemented throughout the process to ensure the consistent production of high‑quality drug substance.
The drug product is provided as a solution in a 3 mL Type I clear glass cartridge (the primary container) that gets further assembled into a prefilled pen. The solution contains 1.2 mL deliverable volume of somatrogon at a concentration of 20 mg/mL or 50 mg/mL.
The manufacturing process of the drug product begins with the thawing of drug substance, followed by compounding, dilution, filtration, and aseptic filling steps. A cartridge plunger stopper is inserted aseptically into each cartridge immediately after filling, and then the cartridges are visually inspected prior to pen assembly, labeling, and packaging.
The sponsor has demonstrated that the drug product manufacturing facility is capable of consistently producing Ngenla of acceptable quality. Controls of critical steps of the drug product manufacturing process were appropriately defined throughout development, based on a risk assessment and current process understanding.
None of the non‑medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.
Control of the Drug Substance and Drug Product
An appropriate control strategy, including in‑process controls and parameters, control of raw materials, and specifications, has been established to ensure the consistent production of high quality drug substance and drug product. The drug substance and drug product specifications include validated assays for identity, quantity, purity, potency, impurities, and safety. Analytical methods are validated according to International Council for Harmonisation guidelines and are in compliance with the respective Pharmacopeia (the European Pharmacopoeia and the United States Pharmacopeia).
Results from process validation studies indicate that the 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.
Ngenla is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per Health Canada's 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 36‑month shelf life for Ngenla is considered acceptable when stored at 2 °C to 8 °C, with an in‑use period of 28 days after the first use, but not exceeding the original expiration date. Each use can only be exposed to no more than 32 °C for a maximum of two hours and a maximum of five times during the in‑use period of 28 days.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing. The container closure system met all validation test acceptance criteria. The proposed packaging and components are considered acceptable.
Facilities and Equipment
Based on a risk assessment score determined by Health Canada, on‑site evaluations of the drug substance and the drug product manufacturing facilities were not deemed necessary.
Both sites involved in production are compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Purification process steps designed to remove and inactivate viruses are adequately validated.
A material of animal origin, FuGENE 6, was used in the development of the recombinant cell line. Raw materials of animal and recombinant DNA origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the final product formulation are not of animal or human origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| NGENLA | 02521679 | PFIZER CANADA ULC | SOMATROGON 20 MG / ML |
| NGENLA | 02521687 | PFIZER CANADA ULC | SOMATROGON 50 MG / ML |