Topical Ophthalmic Drug Products Quality Considerations – Guidance for Industry

In the intricate realm of pharmaceuticals, where precision and safety are paramount, the FDA’s “Quality Considerations for Topical Ophthalmic Drug Products Guidance for Industry” serves as a beacon. Topical ophthalmic drugs play a pivotal role in managing ocular conditions, ranging from infections to glaucoma. Ensuring the quality of these products is not just a regulatory requirement but a commitment to patient safety and efficacy. This blog explores the useful aspects outlined in the guidance, shedding light on the FDA’s proposed approach for topical ophthalmic drug products. 

Microbiological Considerations for Topical Ophthalmic Drug Products: 

Microbial contamination poses a significant risk to ophthalmic drug products. Our exploration of the guidance includes the following considerations: 

  1. Product Sterility: The manufacturers of sterile drug products must comply with cGMP requirements to ensure product sterility.  
  1. Multidose Drug Products: Multidose CCS are more prone to microbial contamination than unit dose CCS as they are opened multiple times between doses over the course of their shelf life. If a multidose drug product does not possess inherent antimicrobial activity, an appropriate preservative is an alternative. However, FDA does not recommend using silver sulphate or other silver-containing compounds due to safety concerns such as argyria. 

Visible Particulate Matter – Inspection program for Topical Ophthalmic Drug Products: 

There should be a robust visual inspection program and the implementation of CGMP requirements are important to ensure topical ophthalmic products are not adulterated. Both compendial and non-compendial ophthalmic drug products should meet the requirements in USP General Chapter <771> Ophthalmic Products. 

Extractables and Leachable 

Extractables and leachable can come from primary, secondary and tertiary packaging components of CCS including semipermeable CCS. Leachable have the potential to interact with the formulated drug product, which could compromise product quality and therapeutic effect of ophthalmic drug products. Manufacturers should refer to the USP General Chapters for the general tests of CCSs. 

  1. Extractables: Manufacturers should document extractable studies to meet cGMP requirements. The applicants should provide information such as a risk assessment, data from extractable studies, the use of extraction conditions (e.g., media, temperature, time etc.), analytical procedures (e.g., gas or liquid chromatography-mass spectrometry) including method validation, assessment of the resultant extractable profiles etc. 
  1. Leachable: Manufacturers should document leachable studies to meet cGMP requirements. The applicants should provide information such as data from three primary stability batches as described in USP General Chapter <1664>, analytical procedures (e.g., gas or liquid chromatography-mass spectrometry) including method validation, assessment of the resultant leachable profiles, acceptance criteria contained in drug product specifications. 

Impurities and Degradation Products 

A scientifically sound and appropriate specifications should be established to comply with 21 CFR 211.160(b) which includes identifying test methods and acceptance criteria for impurities and degradation products.  

In vitro Drug Release/ Dissolution Testing for Quality Control 

The use of in vitro drug release from ophthalmic drug products (i.e. dissolution testing) can be considered as a part of quality control strategy for certain ophthalmic dosage forms (e.g., suspensions, emulsions, semi-solids). The applicant should provide scientific justification for how the control strategy will ensure consistent product quality. 

CCS Design and Delivery and Dispensing Characteristics 

The integrity of container closure systems (CCS) is paramount in not only preserving the potency of ophthalmic drugs but also to prevent the in-use contamination of ophthalmic drug products, which must be supported by stability data. 

  1. CCS Design 

If the CCS that holds or contains an ophthalmic drug also delivers it, it may be considered as a combination product and are subject to the CGMP requirements under 21 CFR part 4, subpart A. 

  1. Tamper-Evident Packaging: All containers of ophthalmic drug products including OTC drugs must be sterile at the time of filling and closing and sealed. 
  1. Tips: There should be single-step procedures that involve simple directions and twisting the cap without removing it. 
  1. Torque Specifications: Torque should be low enough so that special populations e.g., elderly, but high enough so that caps remain in place during manufacturing, storage, shipping, and handling. 
  1. Color Coding: Color coding the caps of ophthalmic drug products is an effective tool in characterizing their therapeutic class. 
  1. Delivery and Dispensing Characteristics 

For all topical ophthalmic drug products, FDA recommends following fill volume of unit dose (non-preserved) and drop size of multidose containers for, ointment or gel:

Type of Container Type of Ophthalmic Drug Product Fill Volume Drop Size 
Unit Dose CCS Solutions, emulsions, suspension 0.5 ml Not Applicable 
Unit Dose CCS Ointment or gel 1 gram Not Applicable 
Multidose CCS All topical ophthalmic drug products Not mentioned 20 to 70 microliters 

ANDA submissions should include information on the measurement of drop volume/drop weight and testing conditions, such as the number of drops in the container and its holding angle during dosing. 

Stability Studies – Establishing a program for ophthalmic drug products: 

Stability studies form the backbone of ensuring a product’s longevity and efficacy. Manufacturers must establish a program to evaluate the stability of ophthalmic drug products and to use the results of the stability testing to determine appropriate storage conditions and expiration dates. There are several stability recommendations including container orientation during storage, water loss for ophthalmic drug products packaged in semipermeable CCS, freeze/thaw study for emulsions and suspensions and last in-use stability study. 


As we navigate the landscape of quality considerations for topical ophthalmic drug products guided by the FDA’s expertise, it becomes evident that these guidelines serve as more than regulatory benchmarks. They are a testament to a shared commitment to excellence in the pharmaceutical industry, where patient well-being is the ultimate vision. By embracing and implementing these quality considerations, we not only meet regulatory expectations but also elevate the standard of care for those relying on these vital ophthalmic interventions.