Common deficiencies found in generic Finished Pharmaceutical Product (FPP) applications submitted for registration to the South African Health Products Regulatory Authority (SAHPRA)

Background The aim of the study was to investigate the common deficiencies observed in the Finished Pharmaceutical Product (FPP) section of generic product applications submitted to SAHPRA. The study was conducted retrospectively over a 7-year period (2011–2017) for products that were finalised by the Pharmaceutical and Analytical pre-registration Unit. Methods There were 3148 finalised products in 2011–2017, 667 of which were sterile while 2089 were non-sterile. In order to attain a representative sample for the study, statistical sampling was conducted. Sample size was obtained using the statistical tables found in literature and confirmed by a sample size calculation with a 95% confidence level. The selection of the products was according to the therapeutic category using the multi-stage sampling method called stratified-systematic sampling. This resulted in the selection of 325 applications for non-sterile products and 244 applications for sterile products. Subsequently, all the deficiencies were collected and categorised according to Common Technical Document (CTD) subsections of the FPP section (3.2.P). Results A total of 3253 deficiencies were collected from 325 non-sterile applications while 2742 deficiencies were collected from 244 sterile applications. The most common deficiencies in the FPP section for non-sterile products were on the following sections: Specifications (15%), Description and Composition (14%), Description of the Manufacturing Process (13%), Stability Data (7.6%) and the Container Closure System (7.3%). The deficiencies applicable to the sterile products were quantified and the subsection, Validation and/or Evaluation (18%) has the most deficiencies. Comparison of the deficiencies with those reported by other agencies such as the USFDA, EMA, TFDA and WHOPQTm are discussed with similarities outlined. Conclusions The overall top five most common deficiencies observed by SAHPRA were extensively discussed for the generic products. The findings provide an overview on the submissions and regulatory considerations for generic applications in South Africa, which is useful for FPP manufacturers in the compilation of their dossiers and will assist in accelerating the registration process.

Stability Testing of Pharmaceutical Products

Stability studies must be carried out according to the guidelines provided by the International Conference of Harmonization, World Health Organization, and other agencies in a scheduled manner. The pharmaceutical product’s stability can be defined as the ability, within its physical, chemical, microbiological, toxicology, protective, and informational requirements of a particular formulation in a specific container-closure system. It also guarantees that the performance, safety, and efficacy are maintained throughout the shelf life of any pharmaceutical product which is considered as pre-requisite for acceptance and approval. Different stability test methods have originated with the need for constant monitoring of drugs and products for their quality and purity. In this review, we have included the types of stability of drugs substances, the relevance of different methods used to test the stability of the pharmaceutical product, guidelines issued to test the stability of pharmaceuticals, stability testing protocols which describes the main components of a well-controlled and regulated stability test and other aspects of stability.

Integrity performance assessment of a Closed System Transfer Device syringe adaptor as a terminal closure for Luer-Lock syringes.

Objectives To investigate the container closure integrity of a Closed System Transfer Device syringe adaptor lock in combination with disposable Luer-Lock syringes as the terminal closure device. The UK NHS Pharmaceutical Quality Assurance committee requires syringe integrity data for final storage devices of aseptic products such as chemotherapy drugs when prepared in advance and stored prior to use as is standard practice for dose banded drugs. The assessment comprised both physical and microbial integrity testing of the combination closed system/ Luer-Lock syringes containers at syringe sizes: 1mL, 20mL, and 50mL. Methods Integrity testing was performed as described in the NHS Pharmaceutical Quality Assurance Committee Yellow Cover Document 2nd edition 2013 with ChemfortTM (Simplivia, IL) syringe adaptor lock devices as replacement for sterile blind hubs. Microbiological integrity was assessed according to Method 1 part 1.4 using Brevundimonas diminuta at 32oC for up to 14-days contact time. Physical integrity was assessed using Method 3 of the yellow cover document which is a dye intrusion method. Dye intrusion was assessed both visually and using a validated ultraviolet-visible spectrophotometer method. Results ChemfortTM syringe adaptor lock/ Luer-Lock syringe combinations were shown to be: (1) free of microbiological contamination after 14-days contact time, (2) free of dye intrusion at all syringe sizes tested (n=61 in total). The data demonstrates 100% closure integrity of the final container system when ChemfortTM syringe adaptor lock replaces the syringe hub as the terminal closure device. Conclusions Syringe adaptor lock components complied with the NHS Pharmaceutical Quality Assurance Committee Yellow Cover Document syringe integrity requirements when used as the terminal closure of Luer-Lock disposable syringes from 1mL up to 50mL. Therefore, syringe adaptor lock (ChemfortTM) can be used as the terminal closure system for pre-filled syringes of chemotherapeutic drug products prepared in advance in UK NHS Pharmaceutical Technical Services.

Challenge of polymers for biosimilar products packaging

Presently Packaging plays a significant role for Biosimilar product. The process of selecting materials and the type of packaging also offers an opportunity for the Packaging scientist to look for new biological delivery choices. Most injectable protein products were supplied in some sort of glass vial, prefilled syringe, and cartridge. Those product having high Ph content there is a chance of “delamination “from inner surface of glass vial. With protein-based drugs, the biggest issue is the effect of packaging derivatives on the protein’s three-dimensional and surface structure. These are any effects that relate to denaturation or aggregation of the protein due to oxidation or interactions from contaminants or impurities in the preparation. The potential for these effects needs to be carefully considered in choosing the container and the container closure system to avoid putting patients in jeopardy.

Container Closure and Delivery Considerations for Intravitreal Drug Administration

Intravitreal (IVT) administration of therapeutics is the standard of care for treatment of back-of-eye disorders. Although a common procedure performed by retinal specialists, IVT administration is associated with unique challenges related to drug product, device and the procedure, which may result in adverse events. Container closure configuration plays a crucial role in maintaining product stability, safety, and efficacy for the intended shelf-life. Careful design of primary container configuration is also important to accurately deliver small volumes (10-100 μL). Over- or under-dosing may lead to undesired adverse events or lack of efficacy resulting in unpredictable and variable clinical responses. IVT drug products have been traditionally presented in glass vials. However, pre-filled syringes offer a more convenient administration option by reducing the number of steps required for dose preparation there by potentially reducing the time demand on the healthcare providers. In addition to primary container selection, product development studies should focus on, among other things, primary container component characterization, material compatibility with the formulation, formulation stability, fill volume determination, extractables/leachables, and terminal sterilization. Ancillary components such as disposable syringes and needles must be carefully selected, and a detailed administration procedure that includes dosing instructions is required to ensure successful administration of the product. Despite significant efforts in improving the drug product and administration procedures, ocular safety concerns such as endophthalmitis, increased intraocular pressure, and presence of silicone floaters have been reported. A systematic review of available literature on container closure and devices for IVT administration can help guide successful product development.

Physical environments of water containers and Aedes sp larvae in dengue endemic areas of Tanjungpinang Timur District

Purpose: This study aimed to determine the relationship of the container environment's type and condition to the existence of Aedes sp larvae in Tanjungpinang Timur District. Methods: An observational study with a cross-sectional approach involved 401 houses with containers in Tanjungpinang Timur District, Tanjungpinang City. Data on the existence of larvae was performed using the single larvae method. Data on container type and container environmental conditions (water pH, water temperature, air temperature, air humidity) and larvae's presence were collected by observing and measuring. Results: 863 containers were observed, 138 of them (15.99%) were found larvae of Aedes sp, containers inside the house (65.57%), and not closed (88.53%). The types of containers were controllable sites (95.13%), disposable sites (3.36%), and under controllable sites (1.51%). The measurement of water pH (76.13%) and water temperature (82.73%) of the containers were categorized as good. Container temperature 98.38% showed results with a range of unfavorable conditions (<200C &> 300C) and air humidity of 99.07% with a range (<81.5% &> 89.5%). Type, location, condition of container closure, water pH, water temperature, and air temperature of containers were related to larvae in Tanjungpinang Timur District (p-value <0.05), while the variable humidity was not related to the existence of larvae. Conclusion: Physical environmental factors strongly support the reproduction of DHF vectors in the East Tanjungpinang District. It is necessary to increase public knowledge and routine home eradication of mosquito nests (PSN), especially controllable site containers widely used as water reservoirs.