Smita Rajput, Field Marketing SAFC Portfolio, MilliporeSigmaOphthalmic drug formulation and manufacturing brings with it unique challenges and regulatory requirements.
Pharma Manufacturing recently spoke with Smita Rajput, Field Marketing Manager at MilliporeSigma about important factors to consider.
Q: What is driving growth in the ophthalmic drug market?
A: The driving forces for the market are the rise in the geriatric population as well as in age-related eye disorders. This has caused a surge in demand for ophthalmic drugs, and an increase in R&D and clinical study investment by various pharma companies. Added to that, we see government initiatives to raise awareness about eye diseases and treatments.
Q: What are the different types of ophthalmic drug delivery systems?
A: Ophthalmic drugs can be administered in four ways. The drugs can be administered through intravitreal injection, subconjunctival injection, subretinal injection or topical administration.
The topical drug delivery system is one of the noninvasive routes of administration and has minimum side effects. Topical administration also delivers therapeutic drugs in the anterior segment of the eye, so in the case of ophthalmic topical formulations, there are different types of drug deliveries available including solutions, emulsions, suspension, gels, in situ gels and ointments.
Q: What are some important considerations for ophthalmic drug formulations?
A: Ophthalmic drug delivery systems, including topically administered solution dosage forms, need to be sterile and free from visible particles. These formulations should also be isotonic with ophthalmic fluid. Otherwise, they result in irritation to the eye surface. In many cases, ophthalmic dosage forms are multi-use or they can be used over some time, so they need to be protected from microbial contamination during the in-use period.
Q: What are some of the biggest regulatory challenges of ophthalmic drug delivery systems?
A: Recently, regulatory authorities — specifically the U.S. FDA — have started considering ophthalmic formulations designed for administration as eye drops to be drug-device combination products. The regulatory compliance requirements for such combination products are much more complex than those for the drugs alone.
In addition to that, the FDA publishes product-specific bioequivalence recommendations to assist the generic pharmaceutical industry with identifying the most appropriate methodology for developing generic drugs and generating the evidence needed to support Abbreviated New Drug Application approvals. Since 2008, the FDA has posted numerous of these product-specific bio recommendations for ophthalmic drug products.
These recommendations describe different types of bio studies like clinical, pharmacokinetics, as well as in vitro that can be conducted for specific ophthalmic drug products. Ophthalmic product developers must fulfill all these product-specific requirements.
Q: Why is the API selection for ophthalmic drugs so important?
A: Bioavailability is a critical aspect of any type of drug delivery, and achieving bioavailability for BCS class II and class IV APIs is very challenging due to their limited water solubility. When designing ophthalmic drug formulations, a common technological problem is the low solubility of the active substance, which makes it impossible to achieve the desired therapeutic concentration if no countermeasures are applied. Also, suspension is not always an option due to irritant effects.
Hence, different solubility-enhancing technologies can be used which include cyclodextrin complexation, nanosuspension or nanoemulsion, co-solvent or micellar solubilizers. If you don’t have options because you have to use the same BCS class II and IV drugs, then you need to look from the excipient or technology point of view in terms of what can be done to enhance the solubility of such APIs.
Q: What needs to be taken into consideration for the selection of excipients and filters when developing a manufacturing process for ophthalmic products?
A: Excipients play a very important role in the development of any dosage form. They have a direct impact on critical quality attributes, as well as critical process parameters of the manufacturing process.
Preservatives are a great example. They are used to protect the ophthalmic product from microbial contamination, but the quality and the impurity profiling of these preservatives will impact the critical quality attributes of the product — like stability or preservative efficacy.
Similarly, excipients impact the manufacturing process. For example, benzalkonium chloride tends to get absorbed into the filter membrane which can result in loss of preservatives, leading to lower concentration of the preservative in final drug product, and that affects the preservative efficacy.
To resolve this challenge, either the filter flush volume or the filter hold time needs to be increased. Both these approaches increase the manufacturing time with less yield. Here process efficiency gets compromised. In our R&D, we conducted several studies with our preservatives and filters with MOC of PVDF and PES against other marketed filters. We observed that the Millipore® Express filter membrane showed less adsorption and that the membrane gets saturated faster than other filter membranes. If a drug manufacturer is working on ophthalmic formulations with benzalkonium chloride as a preservative, then they can leverage our Millipore® Express SHF membrane to get a higher yield and reduce processing time.
Q: How are polymers used in ophthalmic formulations?
A: Polymers offer several benefits for drug forms. They can increase the contact time with the target tissue and reduce the drainage of the solution. Polymers also help to enhance the efficacy of the drug — if its viscosity is initially too low, polymers can help to further sustain the release of the active drug substance. They can act as solubilizers, inhibit crystallization and serve as a lubricant.
A variety of polymers can be used in ophthalmic formulations, including those of natural, synthetic or semisynthetic origin. In addition to selecting the right polymer for the formulation, aspects related to preparing the polymer solution, sterilization, and interaction with the other excipient in the final formulation must also be considered.
Q: What advantages does polyvinyl alcohol offer?
A: Polyvinyl alcohol (PVA) is a biocompatible synthetic polymer produced by the polymerization of vinyl acetate and partial hydrolysis of the resulting esterified polymer. PVA has been used in approved drug products and is generally recognized as safe (GRAS) by the FDA, does not have any immunogenic effects, and its long-term use has been demonstrated in many different formulations including oral, topical and ophthalmic.
It is water soluble, has a narrow range of viscosity, and has a high degree of swelling, offering the precise viscosity needed for formulations to remain in the eye cavity. The polymer has high adhesion and high correlation properties and also forms a transparent solution, which is important for medications administered to the eye. These are also important for retention in the eye cavity. With excellent lubricant activity, this polymer is well suited for lubricating eye drops.
Finally, PVA acts as a precipitation inhibitor of crystallization which means it helps retain the solubility of the API throughout the storage of the dosage form. With PVA being synthetic in nature, you can ensure that every batch will have high reproducibility which is very important for the ophthalmic dosage form.
Q: How is MilliporeSigma supporting the pharma industry in regards to ophthalmic drug delivery?
A: The SAFC® portfolio offers many products which can be used to manufacture sterile ophthalmic formulations, including a wide variety of excipients specifically designed for sterile formulations, aseptic filters, single-use systems, sterile connectors as well testing services for QC purposes.
For biologics, we developed a proprietary technology based on excipient combinations to reduce viscosity and maintain stability. Our R&D is continuously focusing on the ophthalmic sector to resolve the current challenges of our customers. Also, we are aware of the needs and challenges in the ophthalmic sector and support our customers not only with products but also with information needed to fulfill regulatory requirements and for risk assessment. In this evolving market and with increasing regulatory demands, we believe that having a strong and reliable supplier as a partner is a key element for success.