The FDA guidance discusses on quality considerations for ophthalmic drug products (i.e., solutions, suspensions, emulsions, gels, ointments, and creams) intended for topical delivery in and around the eye.
The guidance specifically discusses on:
- Approaches to evaluating visible particulate matter, extractables and leachables, and impurities and degradation products.
- Use of in vitro drug release/dissolution testing as an optional quality control strategy for certain ophthalmic dosage forms.
- Recommendations for design, delivery, and dispensing features of container closure systems (CCSs).
- Recommendations for stability studies.
The guidance provides recommendations on the documentation to be submitted in the chemistry, manufacturing, and controls (CMC)/Module 3 section of new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs), including BLAs for biosimilar and interchangeable biosimilar products.
VISIBLE PARTICULATE MATTER
For topical ophthalmic drug products packaged in opaque containers, appropriate technologies (e.g., X-ray spectroscopy) or destructive testing should be used to identify particulates within the accepted visible size range.
EXTRACTABLES AND LEACHABLES
The assessment of extractables and leachables should consider the primary, secondary, and tertiary packaging components of the CCS, including the labeling components.
Semi-permeable CCSs can over time leach low molecular weight compounds (e.g., plasticizers, lubricants, pigments, stabilizers, antioxidants, binding agents) from CCS components or from labeling components (e.g., inks, adhesives, varnishes) into the drug product.
Extractables Studies
Applicants should provide the below information in their application
- A risk assessment in support of the study approach.
- Data from their extractables studies and should take into account the primary, secondary, and tertiary packaging components.
- Information on the use of extraction conditions (e.g., media, temperature, time, analytical techniques).
- Information on the use of analytical procedures (e.g., gas or liquid chromatography–mass spectrometry), including method validation information.
- An assessment of the resultant extractables profiles.
Where a CCS has been used in an approved ophthalmic drug product, an applicant can refer to previously submitted information to address the recommendations above, when feasible and with adequate justification.
Leachables Studies
Applicant should have adequate data to identify and characterize the potential risks associated with the leachables from the CCS and describe how these risks are mitigated, such as by conducting leachables studies.
- Data from three primary stability batches, each of which generally should be followed through expiry as described in USP General Chapter <1664>.
- Information on the use of analytical procedures (e.g., gas or liquid chromatography–mass spectrometry), including method validation information.
- An assessment of the resultant leachables profiles.
- The acceptance criteria presented in drug product specifications.
In addition to the leachables studies, a separate toxicological risk assessment of the leachables should be conducted.
Safety Thresholds
Applicant should assess compatibility and safety concerns of any potential leachables exceeding the qualification threshold. The safety assessment should address the ocular toxicity and irritancy potential of such leachables, in addition to systemic safety.
Applicants can use a safety threshold approach to assess the potential of leachables and extractables to leach into and/or interact with the formulated drug product.
The following recommended leachables thresholds are expressed in parts per million (ppm) (i.e., the parts of a leachable per unit mass of the ophthalmic drug product):
| Threshold | Limits |
| Reporting Threshold | 1 ppm |
| Identification Threshold | 10 ppm |
| Qualification Threshold | 20 ppm |
IMPURITIES AND DEGRADATION PRODUCTS
Generally, NDA and ANDA applicants should follow the principles of reporting, identifying, and qualifying degradation products and impurities outlined in the International Council for Harmonisation (ICH) guidance.
- Each specified identified degradation product or impurity as a percentage of the active pharmaceutical ingredient (API).
- Each specified unidentified degradation product or impurity as a percentage of the API.
- Any individual unspecified degradation product or impurity.
- Total degradation products or impurities.
There are two reasons for the differences in recommended thresholds compared to the ICH recommendations:
- Ophthalmic drug products are directly administered to the eye, and direct, local application has the potential to produce high local concentrations in the eye.
- The differences account for the fact that less is known about the potential effects of individual unspecified degradation products or impurities than specified degradation products or impurities.
| Drug Product Strength (%w/v) | Recommended IT and QT |
| Greater than 0.1% to less than or equal to 1%** (> 0.1% to ≤ 1%) | 0.1% |
| Less than or equal to 0.1% (≤ 0.1%) | 1% or 1 ppm |
IN-VITRO DRUG RELEASE/DISSOLUTION TESTING FOR QUALITY CONTROL
The rate and extent of drug release from ophthalmic drug products are quality criteria that may reflect aspects related to formulation and process variants that are important to control to ensure consistent quality.
The applicant should provide scientific justification for how the control strategy will ensure consistent product quality.
CCS DESIGN AND DELIVERY AND DISPENSING CHARACTERISTICS
When the CCS that holds or contains an ophthalmic drug also delivers it, it may also be a device constituent part and, together with the drug contained within a combination product.
CCS Design
Tamper-Evident Packaging
All containers of ophthalmic drugs must be sterile at the time of filling and closing and sealed to prevent product use without destruction of the seal.
Tips
For CCS designs in which the tip is sealed until opening, multistep procedures are discouraged because a patient may touch and contaminate the tip with their hands while attempting to unseal it.
Torque Specifications
Applicants and OTC manufacturers should consider the torque specifications for drug product CCSs because some patients may have difficulties twisting off CCS caps that require extra effort to open.
Color Coding
Color coding the caps of ophthalmic drug products is an effective tool in characterizing their therapeutic class.
FDA recommends that applicants and OTC manufacturers use a uniform color-coding system as described in the American Academy of Ophthalmology’s Color Codes for Topical Ocular Medications policy statement.
Delivery and Dispensing Characteristics
1. Unit Dose Containers
For all topical ophthalmic drug products, FDA recommends that the maximum fill volume of a unit dose (non-preserved) container be no more than 0.5mL for solutions, emulsions, and suspensions. FDA also recommends that the maximum fill for a unit dose ointment or gel be no more than 1 gram. Unit dose containers should not be able to be recapped.
Multi-dose Containers
a. Drop size
For all topical ophthalmic drug products, FDA recommends that the drop size in a multi-dose CCS be between 20 and 70 microliters.
For ophthalmic drug products submitted for approval under an ANDA, applicants should conduct a one-time drop volume/drop weight study to determine drop size during delivery or dispensing. 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 drop size of 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.
Dose uniformity of suspension drug products
As recommended in USP General Chapter <771> Ophthalmic Products—Quality Tests, a re-suspendibility/redispersibility test should be performed for all ophthalmic suspension drug products.
For multi-dose containers, data for a one-time dose-uniformity study (from top, middle, and bottom of the container) should be provided from at least three pilot or exhibit batches to demonstrate that the drug substance is uniformly dispersed and the labeled dose can be consistently delivered throughout the shelf life.
STABILITY
Container Orientation During Storage
The stability of ophthalmic drug products can be affected when they are stored under different orientations. Before conducting primary stability studies, NDA applicants should conduct preliminary development work to evaluate storage conditions in two different orientations – an upright position and either an inverted or horizontal position.
Data from this preliminary work should be used to capture and characterize differences in quality attributes, if any, and determine the worst-case orientation. NDA applicants should use this worst-case orientation when conducting stability tests using batches that represent the commercial manufacturing process.
For products submitted for approval under an ANDA, applicants should place primary stability batches in an upright position and either an inverted or horizontal position, and data from both orientations should be provided in the original submission.
Water Loss
For ophthalmic drug products packaged in semi-permeable CCSs, applicants manufacturers should conduct a water loss test to assess the moisture transmission properties of the CCS and the protective properties of any secondary packaging used.
Freeze/Thaw Study for Emulsions and Suspensions
For ophthalmic drug products that are emulsions or suspensions, applicants and OTC manufacturers should perform a one-time freeze/thaw thermal cycling study to evaluate the effects of any high and low temperature variations that may be encountered during shipping and handling, which could affect the quality and performance of the drug product.26 FDA recommends this study consist of three cycles, with temperatures cycling between freezing (-20 °C to 0 °C) and ambient (25 °C to 35 °C) temperatures for a cumulative minimum of 3 days.
In-Use Stability Studies
In-use stability studies are used to determine expiration dates and support labeling claims for appropriate storage conditions that may change after opening, such as a change in temperature or light exposure.