Semi-Solids: A Regulatory Perspective

Semi-solid products have been manufactured for many years for distribution as pharmaceutical drug products, cosmetics and health supplements. The semi-solid drug category is comprised of creams, gels, ointments, suppositories, and other special topical dosage forms.¹ Semi-solid drug formulations share many common attributes which include consistency, dosage uniformity, preservatives, the route of administration and their formulation basis.

Most routes of administration for semi-solid dosage (SSD) form products are predominantly topical or by method of insertion of the drug product into an orifice of the body. Some of the advantages presented by SSD form products are the ability to apply the drug product directly on the affected area and the administration of this dosage form to be readily administered to patients of any age. However, SSD forms also present the challenge of delivering the drug’s active ingredient across the patient’s skin or other physical membrane to reach the target system.

The SSD form products are formed through intricate formulations having complex structural elements. Often, they are composed of two phases—oil and water—one of which is a continuous (external) phase, and the other of which is a dispersed (internal) phase. The active ingredient is often dissolved in one phase. In the event the drug is not fully soluble in a single phase, it is dispersed in both phases, thus creating a three-phase system.

Many of the physical properties of the dosage form depend upon various factors such as:

• Size of the dispersed particles;
• Interfacial tension between the phases;
• Partition coefficient of the active ingredient between the phases; and
• Product rheology or the flow characteristics of these substances.

These factors combined determine the release characteristics of the drug, as well as other characteristics, such as viscosity. A semisolid product achieves uniformity of its active ingredient during its mixing process. Because of the consistency and viscosity of these products, once the active pharmaceutical ingredient (API) is distributed in the manufacturing batch, the API is less prone to segregation than solid dosage formulations.

Drug products topically administered via the skin fall into two general categories, one category for local action as creams, gels, and ointments and the second category being suppositories.

Creams are semisolid emulsion products which are viscous with an opaque appearance.² The consistency and rheological character of the formulation will depend on whether the cream is water in oil (W/O) or oil in water (O/W). Properly designed O/W creams are an elegant drug delivery system, pleasing in both appearance and feel post-application. Each type of cream is good for most topical purposes and is considered particularly well suited for application to open wounds.

Gels are semisolid systems in which a liquid phase is entrapped within a polymeric matrix. This matrix can have a high degree of physical or chemical cross-linking. Gels are aqueous colloidal suspensions in a hydrated form of the insoluble API(s). Many gel products are turbid, as the polymer is present in colloidal aggregates that disperse light. Gels are used for medication, lubrication and other miscellaneous applications.

Ointments are semisolid preparations intended for external application to the skin or mucous membranes. Ointments can be classified into four types depending on the carrier of the drug or base used for its formulation:³

1. Hydrocarbon or oleaginous bases. Main components are petrolatum, white petrolatum, yellow or white ointment, or mineral oil. These bases are emollient, occlusive, and endure on the applied surface for a long time. The hydrophobic nature promotes water retention within the applied surface.
2. Absorbent or anhydrous base. This class of bases may be divided into two groups: the first consists of bases that permit the incorporation of aqueous solutions (small amounts) with the formation of a water-in-oil emulsion (e.g. Petrolatum and Lanolin) and the second group consists of water-in-oil emulsions that permit the incorporation of oil soluble active pharmaceutical ingredients. Absorption bases also are useful as emollients.
3. Emulsion or water miscible base. Emulsion bases may be water/oil (W/O) or oil/water (O/W).  W/O emulsions are emollient, occlusive, may feel greasy, and hard to wash off.  O/W emulsions are not occlusive, do not feel greasy, and clean well with water.
4. Water soluble base. Majority are polyethylene glycol-based. Not occlusive, not greasy, and water-washable. A gel would be a type of water-soluble base.

Suppositories are a solid body drug delivery system of various weights and shapes, adapted for introduction into orifices of the human body.⁴ The external membrane of the suppository will typically melt, soften, or dissolve at body temperature which allows the active ingredient to then be absorbed by the surrounding tissue. Suppository bases usually employed are cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. The suppository base employed has a marked influence on the release of the active ingredient incorporated in it.

Common processes in SSD manufacturing
Materials transfer. The API should be soluble in either the aqueous phase or in the oil phase. It is important that its solubility is quantified to determine the solvent quantities. Dissolving the active ingredient in a portion of the solvent prior to adding this to the larger formulation tank improves its dispersion and the uniformity of the product.
Process controls. Mixing—it is common for several mixing steps to be required as part of the manufacturing process of a semisolid product. The objective of the final mixing step is to achieve product homogeneity.

Homogeneity is demonstrated by taking samples from various locations of the mixing vessel and submitting them for testing such as pH, viscosity, appearance and assay. There are multiple mixing parameters which have a potential to impact final product uniformity which are normally evaluated during development. Depending upon the complexity of the product and/or equipment utilized, it may be beneficial to include the tank and mixer manufacturer in the design phase of mixing unit operations.

Mixing process considerations should include: mixer type; mixing methods (low shear or high shear); and mixing times.

Temperature control. The temperature limits at every stage of the process need to be established. These temperature limits are defined based on the information on the materials and the temperature required at each process and should be evaluated as part of the development of the product prior to its qualification stage. Excessive temperature may cause physical or chemical degradation of the product. Low temperature may not promote proper emulsification of one of the phases. Either temperature extremes can impact the uniformity, appearance and viscosity of the semisolid dosage form. Temperature control should also consider any potential impact in the microbial quality of the product.  

Homogenization. This step is intended to make a uniform mixture, both visually and proper distribution of the active ingredient suspended or dissolved in the internal phase as well as droplet size for emulsions. There are several types of homogenizers that could be used to achieve this objective. These are an open disk mixer which uses very high tip speeds at the blades and a high shear mixer (colloidal mill) which consists of one stationary disk containing a rotating disk. The particle size of the coarse particles is reduced due to shear as the particles pass through the discs. Very high speed or mixing time would provide too much shear to the product impacting its physical and analytical properties while too low values would not achieve the particle size to have a uniform product. 

Vacuum or degassing. This step can be carried out as one of the final steps in the process to eliminate any air entrapped into the product. This entrapped air could impact the product specific gravity, filling weight and dosing application or stability of the product. The bulk product is normally mixed at low speed under the vacuum period. The process parameters to be determined and controlled in this step are the minimum vacuum level and the specific time of vacuum applied.

Filling. The semisolid bulk product can either be transferred to the filler by gravity or pumped.  In the case of a pump, the materials can have a greater chance of some shear effect that may impact the viscosity and the release of the drug, therefore careful selection of filling equipment configuration is important. The transfer of the material should also consider any measure to avoid introducing air into the product. Process parameters to be determined at this process are normally filling weights, filling speed and tube closure parameters.

Stage 3 continued process verification
The expectations of Stage 3 of the FDA’s 2011 Process Validation Guidance⁵ are that the manufacturer verifies that the process is maintained in a state of control and remains within its validated state.

During the Stage 3 process, the manufacturer must develop a quality system that monitors known variations in raw materials, APIs, CQAs, and CPPs. Any process can encounter one or more sources of variation that were not previously encountered or to which the process had not previously encountered. The quality system should be designed to detect unplanned departures from the process as designed.

This data review may include analysis of in-process trends, review of incoming raw materials and other components used throughout the process. Additionally, review of finished product performance both inter and intra batch results should be undertaken.⁶

Post marketing data assessments (PMDA) should be performed to assess that the product remains within a state of control. The PMDA should include the review of data sources such as: product complaints; out of specification reports; process deviations; batch records (including in-process data); incoming raw material records; adverse events report; deviation management; and change control.

Other aspects that the manufacturer should include in Stage 3 reviews are maintenance records of facilities and utilities, calibration programs, PM programs related to process equipment and its corresponding utilities. 

Performing a Stage 3 Continuous Process Verification program is vital to assure your product remains within the approved process and quality parameters. In addition, the FDA expects that Stage III Process Validation programs are part of the overall quality system within your company. As an outcome of these reviews the manufacturer can assure that the product and process has remained under a state of control. In the event a trend indicates otherwise, further actions may be needed, which may include some sort of market action. 

References
1. Parenteral Drug Association, Technical Report No.60-2 Process Validation: A Lifecycle Approach Annex 1: Oral Solid Dosage/Semisolid Dosage Forms, 2017.
2. Tanesh, S., et al., Skin Cream as Topical Drug Delivery System: A Review,
 Journal of Pharmaceutical and Biological Sciences, Volume 4, Issue 5, pages 149-154, September 2016.
3. The Pharmaceutics and Compounding Laboratory, Ointments: Preparation and Evaluation of Drug Release, UNC Eshelman School of Pharmacy; https://pharmlabs.unc.edu/labs/ointments/bases.htm; web accessed May 16, 2018.
4. Hassler, W.H., and Sperandio, G.J., The Formulation of a Water-Soluble Suppository Base, Journal of the American Pharmaceutical Association, Volume 14, Issue 1, Pages 26–27, January 1953. 
5. U.S. Food and Drug Administration, Guidance for Industry: Process Validation: General Principles and Practices. 2011, https://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf
6. U.S. Code of Federal Regulations Title 21 Part 211.180: Current Good Manufacturing Practice for Finished Pharmaceuticals, Subpart J – Records and Reports – General Requirements.

---

José L. Toro, Ph.D.
Lachman Consultants

José L. Toro, Ph.D. is a principal consultant in the compliance practice at Lachman Consultants who has extensive R&D quality, and quality operations experience in the pharmaceutical industry. Dr. Toro specializes in the transformation of quality and technical services organizations including quality systems, global implementations, corporate auditing, technology transfer and plant operations.