[Solution Spotlight] How to overcome challenges in ophthalmic formulations

Ophthalmic drug formulation and manufacturing brings with it unique challenges and regulatory requirements. To discuss methods to overcome these challenges, Pharma Manufacturing Senior Editor Andrea Corona speaks with Smita Rajput, field marketing manager at MilliporeSigma. 

Transcript

Andrea Corona: Ophthalmic drug formulations must address a unique combination of requirements. The nature of the product makes it so that drug makers not only need to ensure quality and drug tolerability, but also take into consideration factors, such as viscosity, sterility and microbiological purity.

My name is Andrea Corona and I'm the senior editor here at Pharma Manufacturing, and you're listening to Off Script the podcast. Today, we'll be discussing how to overcome challenges in ophthalmic formulations through polymer selection.

Joining me today to talk about this is Dr. Smita Rajput, field marketing manager at India, Southeast Asia, and Oceania, [with MilliporeSigma]. She's a liquid formulation expert for parenterals and ophthalmics. Smita has eight years of professional experience working across multiple roles in pharmaceutical product development. Her expertise in the formulation development of injectables in ophthalmics enables her to identify and address unmet market needs. With her expertise, Smita provides consultations for the selection of excipients in the injectable and ophthalmic segment. She has a Ph.D. in pharmaceutics as well.

Welcome, Smita.

Smita Rajput: Thank you, Andrea, for your kind introduction.

Corona: Of course. So let's go ahead and get started on the first question here. There's a lot, I wanna know. The first question is what is driving growth in the ophthalmic drug market?

Rajput: Yeah. So thank you very much for this question.

So, the driving forces for ophthalmic drug market are the rise in geriatric population and age-related eye disorders, surge in demand of ophthalmic drugs, and increasing R&D and clinical studies investment by various pharma companies. And then are few government initiatives out there to raise awareness about IDC waste and its treatments. So, these are the driving factors for the ophthalmic drug market.

Corona: And can you walk us through the different types of ophthalmic drug delivery systems there are?

Rajput: Sure. So, the off drugs can be administered in four ways. It can be an intravitreal injection, then the second can be subconjunctival injections, then the subretinal injection, and then the last one is topical administration.

So, the topical drug delivery system is one of the noninvasive routes of administration and has minimum side effects. And topical administration also delivers the therapeutic drugs in the anterior segment of the eye. So, in the case of ophthalmic topical formulations, there are different types of drug deliveries are available, including solutions, emulsions, suspension, gels, in situ gels, ointments, inserts. So, there are a lot of different drug delivery systems, which can be used in the ophthalmic drug delivery.

Corona: In general, what are some important considerations for ophthalmic drug formulations?

Rajput: Yeah, so the ophthalmic drug delivery systems, including topically administered solution dosage forms, need to be sterile and free from the visible particles. These ophthalmic formulations are to be isotonic with ophthalmic fluid. Otherwise, it results in irritation to the eye surface. Also, many times ophthalmic dosage forms are multi-use or they can be used over a period of time multiple times. And here, there needs to be protection from microbial contamination during the in-use period. So, these are the few important considerations for the ophthalmic drug formulations.

Corona: So, with that in mind, what are some of the biggest regulatory challenges of ophthalmic drug delivery systems?

Rajput: Yeah, so essentially regulatory authorities, specifically the U.S. FDA, have considered the 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 the 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 the Abbreviated New Drug Application approvals.

So, since 2008, the FDA has shared 28 of these product-specific bio recommendations for the ophthalmic drug products. These recommendations describe different types of bio studies, like clinical, pharmacokinetic, as well as in vitro that can be conducted for specific ophthalmic drug products. So, often mid-drug product developers have had to fulfill all these product-specific requirements. So these are a few of the regulatory challenges you can see for ophthalmic drug delivery systems.

Corona: So, my next question is why is the selection of appropriate APIs for ophthalmic drug formulations so important?

Rajput: So, thanks for this question.

Bioavailability is a critical aspect of any type of drug delivery. Achieving bioavailability for BCS class II and class IV is very challenging to its limited water solubility. When designing of the drug formulation, a very common technological problem is the very 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 an irritant effect. Hence, different solubility-enhancing technologies can be used, which include cyclodextrin complexation, nanosuspension or nano emulsion, co-solvent or micellar solubilizers.

So, hence, the selection of APIs is critical, and if you don't have any option besides you have to use the BCS class II or IV drugs, then maybe we need to look from the excipient point of view or from the technology point of view, which can be used for enhancing the solubility of such type of APIs.

Corona: And when developing a manufacturing process for ophthalmic products, what needs to be taken into consideration for the selection of excipients and filters?

Rajput: Yeah, so excipients play a very important role in pharmaceutical development of any dosage form. Excipients have a direct impact on critical quality attributes, as well as critical process parameters of the manufacturing process. So, I would like to give the example of preservatives. So, they are used to protect the ophthalmic product from microbial contamination, but the quality and the impurity profiling of these preservatives will have a direct impact onto the CQA of the drug product like stability or the preservative efficacy.

So, that was from the preservatives or excipients perspective. But at the same time, the excipients also have an impact on the manufacturing process. So, process efficiencies are also one of the important topics which can speed up the manufacturing process. The preservatives, for example, benzalkonium chloride have a tendency to get absorbed onto the filter membrane and it results in loss of preservatives, which leads to less concentration of the preservative in the 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 of these approaches increase the manufacturing time with less yield. Here, process efficiency gets compromised.

So, in our R&D, we conducted several trials with our preservatives and filters with MOC of PVDF and PES against other marketed filters. And we observed that Millipore Express filter membrane showed less absorption and membrane get saturated faster than other market filter membranes. And hence, it is recommended that if drug product manufacturers are working on ophthalmic formulation with benzalkonium chloride as a preservative, then they can prefer to the Millipore Express SHF membrane to get higher yield and less processing time.

So, these are the few examples of where excipients have a major role in the manufacturing process and how we can better select the filters and excipient combination.

Corona: How are polymers used in ophthalmic formulations?

Rajput: Thanks for this question. So, polymers are an important part of the formulation toolbox and offer several benefits for the ophthalmic drug forms. They can increase the contact time with the target tissue and reduce the drainage of the solution. It also helped to enhance the efficacy of the drug. If viscosity is initially too low, polymers can help increase it to sustain the release of the active drug substance, or we call it an active pharmaceutical ingredient. They can act as solubilizers, they inhibit the crystallization, they also stabilize the formulation and serve as a lubricant. A variety of polymers can be used in ophthalmic formulation, 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 excipients in the final formulation must also be considered for ophthalmic formulations with respect to polymers.

Corona: What advantages does polyvinyl alcohol offer?

Rajput: Yeah, so polyvinyl alcohol is biocompatible, synthetic polymer produced by the polymerization of vinyl acetate and partial hydrolysis of the resulting esterified polymer. So, PVA, it's a short form for the polyvinyl alcohol, has been used in approved drug products for decades and has a long history of use in the food and cosmetic industry. It is generally recognized as a safe, which is GRAS by U.S. FDA, and does not have any immunogenic effects, and its long-term use has been demonstrated in many different formulations, including oral topical and ophthalmic.

PVA offers many advantages for ophthalmic formulation. It is water soluble, has a narrow range of viscosity and a high degree of swelling, offering precise viscosity needed for formulations to remain in the eye cavity. This polymer also forms a transparent solution, which is important for medications administered to the eye, as is high adhesion and high correlation properties, which are also important for retention in the eye cavity. With excellent lubricant activity, this polymer is well suited for lubricating eye drops.

Finally, polyvinyl alcohol acts as an inhibitor of crystallization, which means it helps to retain the solubility of the API throughout the storage of the dosage form. This polyvinyl alcohol being synthetic in nature, you can ensure that every batch will have high reproducibility. This is very important for the ophthalmic dosage form, where you will get high consistency for each and every dosage form that you will manufacture. These are the few important advantages for offers for ophthalmic formulations.

Corona: And my last question is how is Millipore Sigma supporting the pharma and biopharma industries with respect to the ophthalmic drug delivery system?

Rajput: Millipore Sigma has a majority of the products which can be used to manufacture this sterile ophthalmic formulation, including a wide variety of GMP grade excipients, specifically designed for the sterile formulations. We also have the aseptic filter, single-use systems, sterile connectors, as well as testing services for the QC purpose. For biologics, to enable the high concentration in low volume for intravitreal application, we have a proprietary technology based on the excipients combinations to reduce the viscosity and increases the stability.

Our R&D is continuously focusing on the ophthalmic sector to resolve the current challenges of our customers. Also, we are very well aware of the needs and challenges in ophthalmic sector and support our customers, not only with high-quality products but also with the high-quality information needed to fulfill the regulatory requirements and for risk assessment. So, in this evolving market and increasing regulatory demands, we believe that having a strong and reliable supplier as a partner is critical as well as the key to the success of our customers.

Corona: Well, thank you for sharing all your insights. It sounds like you're definitely very busy over there at MillporeSigma and you have some exciting things going on. I look forward to hearing about them in the future. Thank you so much for joining me and sharing all your knowledge with us.

Rajput: Thank you very much for giving us an opportunity to share our views about the ophthalmic delivery systems.

Corona: Of course, excited to have you back someday. And for our listeners, this is Andrea Corona, and you've been listening to a special edition of Off Script: A Pharma Manufacturing Podcast. Stay healthy and stay informed.

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