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FDA Guidance Breakdown: Quality Considerations for Topical Ophthalmic Drug Products
The guidance discusses certain quality considerations for ophthalmic drug products (i.e., solutions, suspensions, emulsions, gels, ointments, and creams) intended for topical eye delivery.
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On October 13, the FDA issued new draft guidance recommending a battery of studies that manufacturers should use to assess the quality of topical ophthalmic drugs.
The assessment includes visible particle studies, extractable and leachable studies, container closure system studies, and studies to assess impurities and degradation products.
This draft guidance was issued in response to multiple recent incidents of contaminated eye drops, including an April 2023 warning letter to Pharmedica for making eye drops that could potentially cause blindness. In February 2023, the FDA also notified consumers to stop using sterile eye drops made in India by Global Pharmaceutical Healthcare because of microbial contamination.
The draft guidance covers new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and over-the-counter monograph drugs. It applies to solutions, suspensions, emulsions, gels, ointments, and creams intended for topical delivery in and around the eye.
Below, we’ve summarized the key takeaways from the guidance to inform efficient action among impacted firms. Read the full draft guidance for complete details.
Visible Particulate Matter
A robust visual inspection program is essential, and adherence to CGMP requirements is crucial to ensure that ophthalmic drug products are not adulterated (Page 5).
Technologies like X-ray spectroscopy or destructive testing are recommended for products packaged in opaque containers to identify particulates within the accepted visible size range (Page 5).
Products recognized in the USP must meet the particulate matter requirements in USP General Chapter <771> Ophthalmic Products—Quality Tests. This also applies to noncompendial ophthalmic drug products (Page 5).
For ophthalmic drug products designed with inherent visible particulates, such as suspensions and emulsions, stability testing can evaluate changes in particle size over the product’s shelf life (Page 5).
Extractables and Leachables
Extractables are organic and inorganic chemical entities released from a pharmaceutical packaging/delivery system, packaging component, or material of construction into an extraction solvent under laboratory conditions (Page 14).
Leachables thresholds are expressed in parts per million (ppm), with a reporting threshold of 1 ppm, identification threshold of 10 ppm, and qualification threshold of 20 ppm (Page 8).
OTC manufacturers should document information about their safety thresholds. Applicants should list leachable impurities above the reporting threshold and other impurities in the drug product specification section of NDAs and ANDAs (Page 8).
The differences in recommended thresholds for ophthalmic drug products compared to ICH recommendations are due to the direct administration to the eye and the potential for high local concentrations. Less is also known about the potential effects of individual unspecified degradation products or impurities (Pages 8-9).
Critical quality attributes should be within an appropriate limit, range, or distribution to ensure the desired product quality. These include physical, chemical, biological, or microbiological properties or characteristics (Page 14).
Impurities and Degradation Products
Impurities and degradation products should be identified and controlled, with specifications established in compliance with 21 CFR 211.160(b) (Page 8).
NDA and ANDA applicants are advised to adhere to the principles of reporting, identifying, and qualifying degradation products and impurities as outlined in the ICH guidance for industry Q3B(R2) Impurities in New Drug Products (Page 8).
OTC manufacturers should establish thresholds and acceptance criteria for impurities and degradation products according to USP General Chapter <1086> Impurities in Drug Substances and Drug Products (Page 8).
FDA’s recommended thresholds for individual unspecified degradation products or impurities are different for ophthalmic drug products, considering the direct administration to the eye and the potential for high local concentrations (Page 8).
Safety information should address both local ocular toxicity and general systemic toxicity (Page 9).
For ophthalmic biological products, control of degradation products or product impurities can be based on specific acceptance criteria at release and under storage, considering historical ranges in pivotal clinical trials (Page 9).
In Vitro Drug Release/Dissolution Testing for Quality Control
The rate and extent of drug release from ophthalmic drug products are essential quality criteria, reflecting formulation and process variants that need control for consistent quality (Page 10).
In vitro drug release/dissolution testing is a recommended approach for quality control, especially for ophthalmic dosage forms like suspensions, emulsions, and semi-solids (Page 10).
Applicants can also consider other approaches, such as using critical quality attributes (CQAs) sensitive to formulation and process variants (Page 10).
Scientific justification is required to ensure that the chosen control strategy effectively ensures consistent product quality (Page 10).
CCS Design and Delivery and Dispensing Characteristics
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 (Page 10).
OTC drugs must comply with the tamper-evident packaging requirements of 21 CFR 211.132. Special care is needed for CCS with a nonretaining tamper-evident ring to ensure it does not detach during use, potentially causing an eye injury (Page 10).
For CCS designs where the tip is sealed until opening, multistep procedures are discouraged to avoid contamination from patients touching the tip. Single-step procedures involving simple directions and twisting the cap without removing it are recommended (Page 10).
The torque should be low enough for special populations, including the elderly, to open caps without difficulty but high enough to ensure caps remain in place during manufacturing, storage, shipping, and handling (Page 11).
Color coding the caps of ophthalmic drug products helps in characterizing their therapeutic class. A uniform color-coding system as described in the American Academy of Ophthalmology’s Color Codes for Topical Ocular Medications policy statement is recommended (Page 11).
The maximum fill volume of a unit dose (nonpreserved) container be no more than 0.5 mL for solutions, emulsions, and suspensions to ensure appropriate dosing and minimize waste (Page 11).
Container Orientation During Storage:
The stability of ophthalmic drug products can be affected by different storage orientations. Preliminary development work should evaluate storage conditions in two orientations—an upright position and either an inverted or horizontal position (Page 12).
Data from this preliminary work should capture and characterize differences in quality attributes and determine the worst-case orientation for conducting stability tests with batches representing the commercial manufacturing process (Page 12).
For ANDA products, data from both orientations should be provided in the original submission, and the worst-case orientation should be used for routine stability batches following approval (Page 13).
For products packaged in semipermeable CCSs, a water loss test should be conducted to assess the moisture transmission properties of the CCS and the protective properties of any secondary packaging used (Page 13).
Information on test methods and acceptance criteria used should be documented for OTC manufacturers and included in the application for applicants (Page 13).
Freeze/Thaw Study for Emulsions and Suspensions
A one-time freeze/thaw thermal cycling study should be performed to evaluate the effects of temperature variations encountered during shipping and handling on the quality and performance of the drug product (Page 13).
The study should consist of three cycles, with temperatures cycling between freezing (-20°C to 0°C) and ambient (25°C to 35°C) temperatures for a minimum of 3 days. Quality attributes should be analyzed periodically throughout the study and compared with the control drug product (Page 13).
Applicants using alternative conditions and durations for their tests should provide justification for the test conditions used (Page 13).
In-Use Stability Studies
These 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 (Page 14).
OTC drugs that are stable for at least 3 years, supported by appropriate stability data, are exempt from the expiration date labeling requirement (Page 14).
Accelerated testing programs can be appropriate to establish stability for meeting this requirement (Page 14).
Safety Thresholds for Leachables
Reporting Threshold: Leachables should be reported if they are present at levels of 1 ppm or higher (Page 8).
Identification Threshold: Leachables should be identified if they are present at levels of 10 ppm or higher (Page 8).
Qualification Threshold: Leachables should be qualified if they are present at levels of 20 ppm or higher, and their safety should be evaluated (Page 8).
A few key questions for self-assessment
Here are ten key questions impacted firms company can use to assess their alignment with this guidance. (This is not an exhaustive review list!)
Does the company have a robust visual inspection program in place to ensure products are not adulterated, especially for those in opaque containers?
Has the company evaluated its ophthalmic drug products for extractables and leachables from the Container Closure Systems (CCS)?
Is there detailed documentation of extractables studies and leachables studies, including the risk assessment, data, analytical procedures, and assessments of the resultant profiles?
Has the company established scientifically sound and appropriate specifications for impurities and degradation products, in alignment with the relevant guidelines and regulations?
Is in vitro drug release/dissolution testing being utilized as a quality control strategy, and is there scientific justification for the chosen control strategy?
Does the company consider tamper-evident packaging, tips, torque specifications, and color coding in CCS design?
Are both unit dose containers and multidose containers evaluated for their delivery and dispensing characteristics?
Are stability studies, including container orientation during storage, water loss, freeze/thaw study, and in-use stability studies, conducted and documented?
Does the company adhere to the reporting, identification, and qualification thresholds for leachables as outlined in the guidance?
Is the company consistently reviewing and aligning its practices with the FDA’s current thinking and recommendations, as well as legal requirements, to ensure the quality and safety of ophthalmic drug products?
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