Qbd in Developing Topical Dosage Forms
Publihsed Date: December 05, 2016
Qbd in Developing Topical Dosage Forms
Hitesh V. Chavda
Formulation and Development Department, Research & Development Centre, Lincoln Pharmaceuticals Ltd, Ahmedabad, India
Corresponding author: Hitesh Chavda, Formulation and Development Department, Research & Development Centre, Lincoln Pharmaceuticals Ltd, Ahmedabad, India, Tel: +91-942-747-2354, +91-276-466-5059; E-mail: firstname.lastname@example.org.
Citation: Chavda HV (2017) Qbd in Developing Topical Dosage Forms. Ely J Pharm Res 2(1):106.
In pharmaceutical industry the quality by testing (QbT) system is used to ensure the drug product quality which is an unbending process with its bound specifications for manufactured batches. Flexibility is limited as change at every stage requires submission of a supplement with respect to change to the USFDA (United States Food and Drug Administration). Not like QbT, the quality by design (QbD) concept is an advanced approach to ensure the pharmaceutical products quality. QbD can recognize the critical material attributes (CMAs) and the critical process parameters (CPPs) concerned in product development through extensive scientific understanding of process. The application of QbD approach to topical dosage forms is in the preliminary stages. For a generic topical product, establishing the mandatory pharmaceutical equivalence and therapeutic equivalence with same components in same concentration with same arrangement is an awkward process. As per the ICH guidelines Q8, pharmaceutical QbD is a systematic approach based on sound science and quality risk management that begins with predefined objectives and emphasizes product and process understanding . However, a lot attention is currently focused on the oral dosage forms, it is equally important for the development of generic topical products as well. Agreed that developing a generic topical product is a complicated and lengthy process, employing QbD possibly will ease the course of development. QbD is first and foremost intended to lessen product variation, improve the process efficiency, and cut costs at various stages. QbD improves the speediness of the product launching onto the market . The FDA guidance, for instance pharmaceutical development (ICH Q8), quality risk assessment (ICH Q9), and pharmaceutical quality systems (ICH Q10) draw attention to the approaches to achieving quality product through QbD . QbD provides identification of CMAs and CPPs which ultimately helps to obtain the product with predefined quality.
In designing a topical formulation, a variety of criteria have to be well thought-out. Solubility, melting point, form (solid or liquid, base or salt, polymorph), particle size, particle size distribution of active pharmaceutical ingredient (API) should be considered. In topical formulation excipients also play a critical role as API. Excipient’s solubility, melting point, polymorphic form, solid or liquid state, compatibility with API, certificate of analysis specifications and particle size are important criteria. For topical dosage form its physical and chemical stability is essential and one have to take care of crystallization, sedimentation, phase separation, rheological behaviour, colour variation and volatility. During manufacturing process, processing conditions like mixing speed, mixing type, mixing time, environmental conditions, physical observation and ingredients insolubility should be considered. This is more critical in case of Q3 products where one has to maintain the microstructure arrangement in addition to qualitative (Q1) and quantitative (Q2) components. The presence of preservatives, antioxidants, chelating agents and other additives needs to be taken care off. Packaging of topical products is different from routine packaging like for oral solids or liquids, and needs focus on container closure material type, transparent or amber, plastic or glass storage, loss of solvent and leachable. Generating the quality target product profile (QTPP) and identifying the critical quality attributes (CQAs) are vital steps in designing a generic topical product. Common elements of a QTPP for a topical product includes dosage form, stability, route of administration, drug product quality attributes, physical attributes (rheological behaviour, particle size, globule size), assay, in vitro release, homogeneity or uniformity, pH, preservatives, degradation products, residual solvent, microbial limits, container closure system and package integrity. These QTPP elements are not concerned to specific topical product. In vitro drug release studies of finished topical dosage form are performed to describe performance characteristics as a part of quality control procedure and rationalization for scale-up and post approval changes. Diffusion cells, such as Franz diffusion cells are used for this purpose. At present, in vitro drug release test is hardly ever included in finished product specifications. This test is indirect measures of various associated parameters like uniformity of content, batch-to-batch uniformity, etc. Overall, this test has several reasons to be implemented as a part of QbD.
The most important condition in developing a generic topical product is that it should be competent to warrant pharmaceutical equivalence and therapeutic equivalence with the reference listed drug product (RLD). Pharmaceutical equivalent means if the drug product holds the same active ingredients, same in strength or concentration, same dosage form and same route of administration. Therapeutic equivalent means only if drug product is pharmaceutical equivalents and if it can be likely to have the same clinical outcome and safety profile when administer to patients under the specified conditions in the labelling . The present paradigm to get approval by an ANDA (Abbreviated New Drug Application) applicant is testing and representing therapeutic equivalence to the RLD. On the other hand, the anticipated QbD approach requires the applicants to meet pharmaceutical equivalence and therapeutic equivalence on the basis of defined QTPP .
Quality by design tools includes design of experiment (DoE), risk management, design space, response surface designs, process analytical technology (PAT) etc. When DoE is applied to a topical product development process, the input factors are the attributes of raw material and process parameters (like mixing parameters) and the outputs variables are CQAs (like the pH, viscosity, uniformity, microscopic structure of the product etc). The DoE provides an idea about the optimized process for manufacturing within an acceptable limit to produce a product with quality without fail. Some of the potential risk management tools includes risk management facilitation methods (like flowcharts and check sheets), failure mode effects analysis approach, failure mode effects and criticality analysis approach, fault tree analysis approach, risk ranking and filtering approach, statistical tools, Ishikawa diagram, “what if” analysis approach, etc. The use and manufacturing of a topical drug product necessarily involve several degree of risk as indicated by ICH Q9. The application of design space allows regulatory flexibility and it can be for single/multiunit, or the complete process. Response surface designs such as three-level factorial designs, Box–Behnken design, and central composite design can discover the most favourable processing conditions. Central composite designs are favoured since they are robust. In contrast, use of Box–Behnken design simplifies the experiment execution. PAT is used for the monitoring of the variable processing parameters of inline/online process continuously to confirm that the process is inside the operating space and helps to establish control strategy.
Topical products include a huge amount of excipients. It is essential to consider compatibility between the drug substance and excipients, solvents, and packaging materials. Change in the excipients grade (e.g. molecular weight differences, reactive residues) may lead to unanticipated results. If the applicant of a generic topical product intends to use an excipient which is not listed in the inactive ingredient guide, then it is necessary to justify about the rationale for its usage in the product and provides necessary information about pharmacology and toxicology along with clinical data to the FDA unless the level of usage is less than or equal to 0.1% in the drug product. It is the accountability of the applicant to provide the all relevant information. The drug substance’s source and quality play an important role in designing a topical product. It is advisable to have another source of the drug substance in the incident that the primary source creates problems. Overage for drug substance is permitted up to the level used in the RLD when there is a loss during manufacturing for a generic topical product.
Common solvents or vehicles used in topical formulations are water, isopropyl alcohol, ethyl alcohol, mineral oil, hexylene glycol etc. for the purpose of solvation, solubility enhancement and penetration enhancement. Suspending or gelling agents used are carbomer, silica, magnesium aluminum silicate, cellulose derivatives, sodium alginate, gelatin, carrageenan, polyethylene oxides, etc. for the viscosity modification or matrix formation. For the generic topical drug product it is not necessary to be similar by viscosity to the RLD. Though, the viscosity evaluation of a topical drug product is encouraged as it is a considerable attribute that influences the drug delivery effect. Viscosity measurement at the laboratory as well as scale-up stages is a main criterion for record. Emulsion-based topical semi-solid products are thermodynamically unstable and require emulsifiers for product stabilization. Commonly used emulsifiers are isostearic acid, sodium lauryl sulfate, glycol stearate, glycerylpalmitate, white soft paraffin, dimethyl isosorbide, oleyl alcohol, acrylate copolymer, cetostearyl ether, etc. Emulsifiers reduce interfacial tension and impart both hydrophilic and hydrophobic characteristics, thereby reducing phase separation and improve the stability of formulation. To provide stiffness to topical semisolid product petrolatum, triglycerides, paraffin, polyethylene glycol, lanolin, microcrystalline wax, beeswax, coconut oil, stearyl alcohol, stearic acid, cetyl alcohol, fatty alcohols etc. are used. To enhance the permeation of drug propylene glycol, ethyl alcohol, isopropyl alcohol, oleic acid, etc. are used. They enhance the solubility and thereby drug partition or diffusion across the biological barriers. For water-based topical products a preservative is always a crucial ingredient. Preservatives used are methylparaben, propylparaben, benzyl alcohol, beonzoic acid, etc. which reduce microbial growth and thereby provide stability to the formulation. Other additives like antioxidants or a combination of antioxidants with chelating agent can be used for oxidative problems. Butylated hydroxytoluene and butylated hydroxyanisole are generally used as antioxidants. Sodium hydroxide is used as neutralizer in several formulations. Chelating agents can also be used for product stabilization e.g. Ethylene diamine tetra acetate . Similar to liquids, topical have good rheological properties and consequently are more prone to degradation. They may interact with container and closure system and accelerate instability issues. So, it is sensible for the sponsor of the generic topical product to use the same packaging material as used by the RLD.
There are certain examples which uses QbD concept for the development of topical dosage form. Generic acyclovir topical dermatological creams prepared by Khan et al.  describe the process variability effect on physicochemical characteristics and in vitro performance. Alcalá et al.  showed the production of a pharmaceutical gel using QbD approach. Rathore and Winkle  discussed the genesis of QbD for biopharmaceuticals and other relevant information. There are certain articles which also provides brief about QbD [10,11].
The overall understanding of QbD involves enhanced knowledge of raw materials and manufacturing processes, QTPP, CQAs, risk management, PAT, DoE, control strategy and continual improvement. These all ultimately aim to boost output with quality product in the end. QbD approach which is based on science and risk factor will lead to the development of generic topical products with a high quality.
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- Nomenclature (as excerpted from the Orange Book). Available from: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4137B1_07_Nomenclature.pdf
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Copyright: © 2016 Chavda HV. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.