FDA Releases New Draft Guidance on Quality Considerations for Topical Ophthalmic Drug Products

The U.S. Food and Drug Administration (FDA) has recently published a draft guidance document addressing quality considerations for topical ophthalmic drug products. The guidance provides a comprehensive framework for assessing the quality and safety of these formulations, focusing on several critical areas.

In this article, we will delve into the key aspects highlighted in the FDA’s draft guidance, which includes approaches to evaluating visible particulate matter, extractables and leachables (along with safety thresholds), and impurities and degradation products. Additionally, the guidance outlines the use of in vitro drug release/dissolution testing as an optional quality control strategy for specific ophthalmic dosage forms.

What Are Quality Attributes in Topical Ophthalmic Drug Products?

Quality attributes are the distinctive characteristics and properties that define the efficacy, safety, and overall quality of topical ophthalmic drug products. These attributes encompass various factors, including physical characteristics, chemical composition, sterility, stability, and the integrity of the container-closure system. 

We at GMPInsiders found that these quality attributes play an integral role in determining the product’s success in the market and its therapeutic impact on patients.

Quality Attributes of Topical Ophthalmic Drug Products

Let’s take a closer look at the quality attributes of topical ophthalmic drug products.

Visible Particulate Matter

A crucial aspect of ensuring product safety is the inspection of visible particulate matter. Contaminants in pharmaceuticals, especially ophthalmic drug products, can have severe consequences. Robust visual inspection programs and adherence to Current Good Manufacturing Practices (cGMP) requirements play a significant role in preventing adulteration. 

For topical ophthalmic drug products enclosed in opaque containers, technologies like X-ray spectroscopy or destructive testing are employed to identify particulates within the acceptable visible size range. This step is essential to ensure that no foreign matter is present in the product, thereby safeguarding patient safety.

Extractables and Leachables in Topical Ophthalmic Drug Products 

Extractables and leachables are substances that can migrate from the container-closure system (CCS) into the ophthalmic drug product. This migration can compromise product quality and therapeutic effectiveness. It’s particularly important to consider the primary, secondary, and tertiary packaging components, including labeling elements, within the CCS.

Over time, semipermeable CCSs can release low molecular weight compounds such as plasticizers, lubricants, pigments, stabilizers, antioxidants, and binding agents. These compounds can leach into the drug product, raising potential safety concerns. However, this is less of a concern for products packaged in glass containers.

A. Extractables Studies

For cGMP compliance, over-the-counter (OTC) manufacturers are required to document various aspects of their extractable studies, including a risk assessment, data from the studies following the framework provided by the USP, extraction conditions, and analytical procedures. 

These procedures often involve advanced techniques like gas or liquid chromatography-mass spectrometry, along with method validation information and assessments of the resultant extractable profiles.

 B. Leachables Studies

Leachables can originate from different sources and may depend on the formulation. Manufacturers and applicants should gather adequate data to identify and characterize potential risks associated with leachables. 

This can be achieved through leachables studies that consider data from primary stability batches, analytical procedures, assessments of leachables profiles, and adherence to acceptance criteria contained in drug product specifications.

C. Safety Thresholds

Modern analytical techniques can detect trace amounts of chemicals, making it impractical and unnecessary to identify all detected leachables for safety qualification. However, when it comes to ophthalmic drug products, the risk assessment should address the ocular toxicity and irritancy potential of leachables exceeding specific safety thresholds.

Manufacturers must document information about their safety thresholds and list leachable impurities above the reporting threshold in drug product specifications. The following recommended leachables thresholds are expressed in parts per million (ppm):

• Reporting threshold: 1 ppm.
• Identification threshold: 10 ppm.
• Qualification threshold: 20 ppm.

Impurities And Degradation Products in Topical Ophthalmic Drug Products

A. NDA, ANDA, and OTC Monograph Drugs

In the world of pharmaceuticals, establishing scientifically sound specifications for impurities and degradation products is a crucial aspect of quality control. To adhere to regulatory requirements under 21 CFR 211.160(b), it is essential to identify appropriate test methods and acceptance criteria for these impurities and degradation products.

NDA and ANDA applicants typically follow guidelines provided by the International Council for Harmonisation (ICH), particularly the guidance for industry Q3B(R2) Impurities in New Drug Products. This guidance outlines the principles of reporting, identifying, and qualifying degradation products and impurities.

OTC (Over-The-Counter) drug manufacturers, on the other hand, establish thresholds and acceptance criteria for impurities and degradation products following USP General Chapter Impurities in Drug Substances and Drug Products. 

It’s important to note that the U.S. Food and Drug Administration (FDA) recommends different thresholds for individual unspecified degradation products or impurities in topical ophthalmic drug products compared to the corresponding thresholds provided in ICH Q3B(R2) for drug products that act systemically. These differences arise for two primary reasons.

First, ophthalmic drug products are directly applied to the eye, and this direct local application can result in higher local concentrations within the eye. Therefore, specific safety thresholds are essential to ensure that the localized impact on the eye remains within safe limits.

Second, more is needed to know about the potential effects of individual unspecified degradation products or impurities in ophthalmic drugs compared to specified degradation products or impurities. 

Read our article about different types of impurities in pharmaceuticals and strategies on how to control them.

In Vitro Drug Release/Dissolution Testing For Quality Control

In Vitro Drug Release/Dissolution Testing

One valuable approach that pharmaceutical applicants can employ to maintain quality control is in vitro drug release/dissolution testing. This method involves simulating the release of the active pharmaceutical ingredient (API) from the product under specific conditions, allowing for the measurement of its rate and extent of release. 

For certain ophthalmic dosage forms, such as suspensions, emulsions, and semi-solids, in vitro testing can be particularly useful. It helps assess how the product behaves in a controlled environment, mirroring what happens when administered to patients.

CCS Design And Delivery And Dispensing Characteristics

The safety and efficacy of ophthalmic drug products are paramount in the field of pharmaceuticals. A crucial component of achieving these goals is the design of Container-Closure Systems (CCS) for topical ophthalmic drug products, ensuring their sterility, tamper-evident packaging, and user-friendliness. 

A. CCS Design Considerations for Topical Ophthalmic Drug Products

Tamper-Evident Packaging

Sterility and the prevention of unauthorized product use are fundamental for topical ophthalmic drug products. Containers must be sterile at the time of filling and sealed in such a way that the seal is destroyed upon opening, ensuring that the product remains uncontaminated.

Over-the-counter (OTC) ophthalmic drugs must also adhere to tamper-evident packaging requirements as per 21 CFR 211. Special attention should be paid to nonretaining tamper-evident rings (e.g., collars or bands) that seal the bottle and cap to prevent them from detaching during use, which could pose a risk of eye injury. 

For OTC drugs, tamper-evident rings should include a positive retention mechanism similar to those on disposable plastic beverage bottles to prevent accidental detachment.

Tips

In cases where the tip of the CCS remains sealed until opening, a user-friendly design is crucial. Multistep procedures can be discouraged since patients might touch and contaminate the tip with their hands while trying to unseal it. Single-step procedures are recommended, involving simple directions and twisting the cap without removal.

Torque Specifications

The ease of opening CCS caps is vital, especially for special populations, such as the elderly, who may have difficulties with complex or tightly sealed caps. The torque, or rotational force required to open the cap, should strike a balance. It should be low enough for easy opening by all users but high enough to secure the caps during manufacturing, storage, shipping, and handling.

Color Coding

Color coding the caps of topical ophthalmic drug products is a valuable practice that helps identify their therapeutic class. 

B. Delivery and Dispensing Characteristics

Unit Dose Containers

Maximum Fill Volume: For topical ophthalmic drug products, the FDA recommends that the maximum fill volume of a unit dose container without preservatives should not exceed 0.5 mL for solutions, emulsions, and suspensions. For unit dose ointments or gels, the maximum fill should be limited to 1 gram. Additionally, unit dose containers should be designed in such a way that they cannot be recapped.

Multidose Containers

a) Drop Size: The size of each drop in a multidose container is a crucial consideration for ophthalmic drug products. The FDA recommends that the drop size should fall within the range of 20 to 70 microliters.

The drop size of the generic product should be within ±10% of the drop size for the Reference Listed Drug (RLD) and within the recommended range of 20 to 70 microliters.

b) Dose Uniformity of Suspension Drug Products: The FDA recommends the use of a resuspendability/redispersibility test for all ophthalmic suspension drug products. For multidose containers, a one-time dose-uniformity study should be conducted from the top, middle, and bottom of the container. 

Stability of Topical Ophthalmic Drug Products

A. Container Orientation During Storage

Their storage orientation can influence the stability of topical ophthalmic drug products. It is vital to determine the worst-case orientation to ensure the product’s quality attributes are consistently maintained. 

B. Water Loss

Semipermeable container-closure systems (CCSs) for ophthalmic drug products may allow moisture transmission. Applicants and OTC manufacturers should conduct a water loss test to assess the moisture transmission properties of the CCS and the protective properties of any secondary packaging.

C. Freeze/Thaw Study for Emulsions and Suspensions

Emulsions and suspensions are common forms of ophthalmic drug products, and they may encounter temperature variations during shipping and handling. A freeze/thaw thermal cycling study is recommended to evaluate the effects of these variations on the quality and performance of the drug product. 

D. In-Use Stability Studies

In-use stability studies are essential for determining expiration dates and supporting labeling claims for ophthalmic drug products that may experience changes in storage conditions after opening. These changes can include alterations in temperature or light exposure. 

Conclusion

In conclusion, the FDA’s draft guidance on quality considerations for topical ophthalmic drug products provides valuable insights into the evaluation of visible particulate matter, extractables, and leachables, in vitro drug release testing, container closure systems, and stability studies. 

Adhering to these guidelines is crucial for manufacturers to ensure the safety, efficacy, and quality of topical ophthalmic drug products. By implementing these recommendations, manufacturers can enhance patient safety and contribute to the overall improvement of ophthalmic healthcare.