495 Sample chapter from Remington: Essentials of Pharmaceutics Chapter 26 Parenteral Preparations Michael J. Akers, PhD Parenteral (Gk, para enteron, beside the intestine) dosage forms differ from all other drug dosage forms, because they are injected directly into body tissue through the primary protective systems of the human body, the skin, and mucous membranes. They must be exceptionally pure and free from physical, chemical, and biological contaminants. These re- quirements place a heavy responsibility on the pharmaceuti- cal industry to practice current good manufacturing practices (cGMPs) in the manufacture of parenteral dosage forms and on pharmacists and other health care professionals to practice good aseptic practices (GAPs) in dispensing parenteral dosage forms for administration to patients. Certain pharmaceutical agents, particularly peptides, pro- teins, and many chemotherapeutic agents, can only be given parenterally, because they are inactivated in the gastrointes- tinal tract when given by mouth. Parenterally-administered drugs are relatively unstable and generally highly potent drugs that require strict control of administration to the patient. Due to the advent of biotechnology, parenteral products have grown in number and usage around the world. This chapter focuses on the unique characteristics of par- enteral dosage forms and the basic principles for formulating, packaging, manufacturing, and controlling the quality of these unique products. The references and bibliography at the end of this chapter contain the most up-to-date texts, book chapters, and review papers on parenteral product formulation, manufac- ture, and quality control. OVERVIEW OF UNIQUE CHARACTERISTICS OF PARENTERAL DOSAGE FORMS Parenteral products are unique from any other type of pharma- ceutical dosage form for the following reasons: •฀ All products must be sterile. •฀ All products must be free from pyrogenic (endotoxin) con- tamination. •฀ Injectable solutions must be free from visible particulate matter. This includes reconstituted sterile powders. •฀ Products should be isotonic, although strictness of isoto- nicity depends on the route of administration. Products administered into the cerebrospinal fluid must be isoton- ic. Ophthalmic products, although not parenteral, must also be isotonic. Products to be administered by bolus injection by routes other than intravenous (IV) should be isotonic, or at least very close to isotonicity. IV infusions must be isotonic. •฀ All products must be stable, not only chemically and physically like all other dosage forms, but also ‘stable’ microbiologically (i.e., sterility, freedom from pyrogenic and visible particulate contamination must be maintained throughout the shelf life of the product). •฀ Products must be compatible, if applicable, with IV diluents, delivery systems, and other drug products co-administered. OVERVIEW OF UNIQUE CHARACTERISTICS OF PARENTERAL DOSAGE FORMS 495 FORMULATION PRINCIPLES 496 VEHICLES 496 SOLUTES 496 ADMINISTRATION 499 PARENTERAL COMBINATIONS 499 GENERAL CONSIDERATIONS 499 GENERAL MANUFACTURING PROCESS 500 COMPONENTS 501 WATER FOR INJECTION (WFI) 501 CONTAINERS AND CLOSURES 504 CONTAINER TYPES 504 RUBBER CLOSURES 506 NEEDLES 508 PYROGENS (ENDOTOXINS) 509 PRODUCTION FACILITIES 510 FUNCTIONAL AREAS 510 MAINTENANCE OF CLEAN ROOMS 514 PERSONNEL 514 ENVIRONMENTAL CONTROL EVALUATION 515 PRODUCTION PROCEDURES 517 CLEANING CONTAINERS AND EQUIPMENT 517 PRODUCT PREPARATION 519 FILTRATION 520 FILLING 521 SEALING 523 STERILIZATION 524 FREEZE-DRYING (LYOPHILIZATION) 525 QUALITY ASSURANCE AND CONTROL 528 STERILITY TEST 528 PYROGEN TEST 529 PARTICULATE MATTER EVALUATION 529 CONTAINER/CLOSURE INTEGRITY TEST 530 SAFETY TEST 530 PACKAGING AND LABELING 530