The technology of topical atropine - Q&A with Dr Houman Hemmati and Dr Kumaresh Soppimath

NVK002 is a proprietary, investigational, low-dose, preservative-free atropine eye drop administered nightly. NVK002 leverages what is known about a well-characterized therapeutic agent, atropine, in a new low-dose, preservative-free formulation that is unique for a handful of reasons. First, NVK002 is shelf-stable for at least two years at room temperature. Additionally, it is formulated with standard excipients (inactive vehicle substances), avoiding the use of novel excipients that have not been used in human eyes for many years. Moreover, it is both sterile and preservative-free.

As a formulation scientist who is involved in developing several ophthalmic products and recently the preservative-free, low-dose atropine, the term "preservative-free" is crucial. 

A preservative-free formulation, particularly when referring to atropine eye drops for the paediatric population, signifies a product designed without the inclusion of ingredients that prevent microbial contamination and maintain sterility. Atropine eye drops may be used over an extended period, heightening the importance of minimizing potential irritation and side effects. 

By excluding preservatives, these formulations aim to ensure a more tolerable treatment option for young patients, utilizing single-use vials or innovative packaging solutions to maintain sterility and potency. This preservative-free approach in paediatric ophthalmic care, like with atropine eye drops, underscores the commitment to developing gentle yet effective treatment modalities for sensitive eyes.

Preservative-free does not mean unsterile. Sterility is ensured through adherence to the highest GMP (Good Manufacturing Practices) quality standards, which ensures consistency in commercial manufacturing compared to pharmacy-compounded preparations. You can read more about the FDA standards here.

It is widely recognized that chronic exposure to topical preservatives can be toxic to the ocular surface, as they can disrupt the lipid and mucous layers of the tear film and damage corneal epithelial cells.¹ For this reason, when eyedrops are taken chronically, preservative-free formulations are generally preferred. NVK002 is packaged in single-use, unit dose ampules to avoid the potential long-term toxicity of topical preservatives while maintaining sterility of the product.

Certainly. When comparing the commercial manufacturing process of a product like atropine eye drops in a GMP-certified facility to pharmacy-compounded preparations, several critical differences ensure the commercial product's uniformity, quality, and safety. Firstly, the GMP process is highly standardized, involving strict controls over all aspects from raw materials to final product specifications, ensuring consistency across batches. Pharmacy compounding may introduce variability due to differences in techniques and ingredients' quality.²

Quality assurance is another significant distinction. GMP facilities implement rigorous testing at every production stage, from raw materials to the final product, to confirm it meets all quality standards. Such comprehensive testing protocols might be beyond the scope of pharmacy compounding practices, affecting potentially the compounded product's consistency and safety.

Regulatory oversight is stricter for GMP facilities, with authorities like the FDA or EMA auditing sites and enforcing compliance with international manufacturing standards through regular inspections. This level of scrutiny is typically more rigorous than what applies to pharmacy compounding, impacting the overall quality and adherence to safety standards. 

Additionally, sterile products manufactured under GMP conditions benefit from validated sterile manufacturing processes, crucial for preventing microbial contamination. Pharmacy-compounded preparations, depending on their environment and processes, might not achieve the same sterility assurance levels.

Lastly, GMP-manufactured products are subject to standardized packaging and labelling that enhance product identification, integrity and provide detailed and consistent patient information. This aspect of commercial manufacturing ensures that products are safely delivered to consumers with clear usage instructions, an area where compounded preparations may not consistently match the GMP standards.

In essence, the commercial manufacturing of atropine eye drops in a GMP facility significantly reduces the variability associated with pharmacy compounding, thanks to stringent standardization, quality assurance, regulatory oversight, and attention to sterility and packaging.

NVK002 is sterile, preservative free, and packaged in single use ampules with a limited fill volume that should not be reused once opened. These factors reduce the likelihood of ocular infections and prevent exposure to topical preservatives. Moreover, the long shelf life of NVK002 ensures a stable product is being used. Finally, with unit dose ampules, it is possible for parents to verify that a dose has been used when an ampule has been opened or is missing, something which is more challenging to do with a traditional dropper bottle.

As a professional formulation scientist deeply involved in the development of low-dose atropine solutions, one of the most compelling challenges we've addressed is the stability of the formulation. Eye care professionals might find it surprising that achieving stability in low-dose atropine, crucial for ensuring efficacy and safety over the product's shelf life, requires innovative formulation strategies. At doses as low as 0.01%, atropine is particularly susceptible to degradation,^3,4 which can compromise its therapeutic effectiveness and safety.

To counteract these stability issues, we've employed advanced formulation techniques, including the use of stabilizing agents, unique buffer concentration and optimizing pH levels, to enhance the stability of atropine without compromising its safety profile. Moreover, the development of preservative-free formulations adds another layer of complexity. The incorporation of novel packaging technologies, such as single-use vials also play a vital role in maintaining the integrity of the low-dose formulation. These efforts collectively underscore the sophisticated balance of innovation and rigor required to deliver a product that is not only effective in slowing myopia progression but also stable and safe for long-term use in a paediatric population. Our dedication to overcoming these challenges reflects our commitment to advancing myopia management and improving patient outcomes.