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17.7 Specifications and Regulatory Guidelines
After optimizing the formulation, product specifications have to be finalized by the formulation scientist. Product specifications are used to monitor the product for reproducible manufacturing and also for stability. Specifications include physical and chemical parameters of the formulation with acceptable limits and analytical methods to carry out the tests for these parameters (Figs. 17.1 and 17.2). Guidelines have been issued by the FDA for the Chemistry, Manufacturing, and Controls for a therapeutic recombinant DNA-derived product. Other significant guidance has also been instituted to make the review of manufacturing changes more reliable.
Drug substance and drug product specifications are to be made based on the information gathered during protein manufacturing and development of protein formulation. These will help in determining the identity, purity, and potency of the product.
Identity: Tests for identity are meant to be specific and capable of uniquely identifying the protein in the formulation (or as a substance). These tests are not necessarily meant to be quantitative. Tests like color and pH also offer simple assays to characterize the formulation.
Purity: No single method can be relied upon for the measure of purity of a protein. A combination of methods is usually used to assess purity. Chromatographic methods such as reversed phase HPLC and mass spectroscopy can be combined to assess the
Fig. 17.1 Sample tests conducted on drug substance to assure its identity, purity, and potency. Stability studies, substance development studies, and routine batch analysis are used to finalize the tests and the acceptance criteria
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Fig. 17.2 Sample tests performed on drug products to assure that the drug product is suitable for release. Tests are a combination of physical, chemical, biological, and microbiological tests that help in confirming the identity, purity, and potency of drug products
purity of the protein in the formulation. It is of paramount importance that the method selected to judge the purity of the protein is able to quantify the protein from its degradation products.
Potency: Potency assays are intended to mimic the specific biological activity of the protein. For many products, in vivo assays have been developed, to measure the biological activity of the protein. For example, the human growth hormone is tested by measuring the daily weight gain in rats which are given a daily injection of the hormone (Hoffman and Pisch-Heberle 2000).
The International Conference on Harmonization of Technical Requirements (ICH) is a joint effort by the regulatory authorities of Europe, Japan, and the United States and experts from the pharmaceutical industry in the three geographical regions to develop technical guidelines and registration processes for pharmaceutical products. Many guidelines are provided at the official website of ICH (www.ich. org), which can be accessed to understand the process of product development. Listed below are a few ICH and FDA (www.fda.gov) guidelines that are important for biotechnological products.
1. Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological /Biological Products. ICH.
2. Q5E Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process. ICH.
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3. Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/ Biological Products. ICH.
4. Drug Administration: Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls Information for a Therapeutic Recombinant DNADerived Product or a Monoclonal Antibody Product for In Vivo Use. FDA.
5. Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-Derived Products. FDA.
6. Guidance, Guidance for Industry: Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products. FDA.
7. Guidance, Guidance for Industry: Q1B Photostability Testing of New Drug Substances and Products. FDA.
8. Guidance for Industry – Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products. FDA.
17.8 Conclusions
Visual acuity is sacrificed in millions of patients suffering from a variety of retinal diseases including diabetic retinopathy and macular degeneration. Macromoleculebased anti-VEGF pharmaceuticals have been recently approved by the FDA to treat neovascularization in patients with wet age-related macular degeneration. When designing a protein pharmaceutical for ophthalmic applications, in addition to ensuring that the drug recognizes a specific target, it is important to ensure that the protein drug can be delivered to its site of action in its active form. Delivery to the site of action may be hindered by ocular barriers such as the blood-retinal barriers and vascular clearance mechanisms present at a particular site of administration. Due to differences in these barriers, various routes of ocular administration deliver different quantities of protein drug to the back of the eye. Novel delivery approaches such as PEGylation, protein-secreting implants, and nanoparticles can potentially overcome the drug clearance mechanisms, localize the drug near the target, and maintain the drug in an effective form. Finally, the design of any pharmaceutical product must consider protein formulation development challenges to ensure that the drug is not inactivated during the formulation process and storage. A careful selection of excipients, process parameters, and storage condition will ensure an active protein formulation. With novel delivery systems such as implants and nanoparticles, chronic or noninvasive delivery of proteins to the posterior segment of the eye will likely be realized in the near future. Once novel approaches are developed to enhance and sustain delivery of protein drugs to the posterior segment of the eye, more impetus for the discovery of novel protein-based treatments for back of the eye diseases is anticipated.
Acknowledgments This work was supported by the NIH grants R01EY018940, R01EY017533, and RC1EY020361.
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