Pharmaceutical products process validation

Another relevant guideline is that on manufacture of the finished product, CPMP/QWP/486/95 reissue (adopted April 1996). This includes a number of more detailed points relating to the manufacturing process, some of which should be taken into account in the development pharmaceutics and process validation sections of an application. 

In pharmaceutical manufacturing, process validation is an exercise that requires the contribution from different departments, including quality assurance and quality control. It is a requirement for good manufacturing practice (GMP) to ensure that the final product produced is of the expected quality. 

EudraLex. Quality Guideline 3AQ1A Development Pharmaceutics and Process Validation. Medicinal Products for Human Use Guidelines, vol. 3 (1988). 

This is often times very important for pharmaceutical production processes where interactions among factors are common. Ultimately, DOE allows the experimenter to determine which process factors are to be included in subsequent validation studies. By eliminating the insignificant factors from the validation work, a great deal of time and money can often be saved. In addition, by using DOE to streamline the development work and efficiently characterize the process, the timeline for product development and a successful commercial launch can be shortened significantly. 

H. Mark, G. E. Ritchie, R. W. Roller, E. W. Ciurczak, C. Tso, and S. A. MacDonald, Validation of a Near-Infrared Transmission Spectroscopic Procedure. Part A. Validation Protocols, /. Pharm. Biomed. Anal, 28,251 (2002). G. E. Ritchie, R. W. Roller, E. W. Ciurczak, H. Mark, C. Tso, and S. A. MacDonald, Validation of a Near-Infrared Transmission Spectroscopic Procedure. Part B. Application to Alternate Content Uniformity and Release Assay Methods for Pharmaceutical Solid Dosage Forms, /. Pharm. Biomed. Anal, 29,159 (2002). M. Blanco, M. Bautista, and M. Alcala, API Determination by NIR Spectroscopy across Pharmaceutical Production Process, AAPS PharmSciTech, 9,1130 (2008). A. Peinado, J. Hammond, and A. Scott, Development, Validation and Transfer of a Near Infrared Method to Determine In-Line the End Point of a Fluidised Drying Process for Commercial Production Batches of an Approved Oral Solid Dose Pharmaceutical Product, /. Pharm. Biomed. Anal, 54,13 (2011). 

Raffin, R. P., Jornada, D. S., Re, M. L, Pohimann, A. R. Guterres, S. S. (2006). Sodium pantoprazole-loaded enteric microparticles prepared by spray drying Effect of the scale of production and process validation. International Journal of Pharmaceutics, Vol. 324,1, (October 2006), pp. (10-18), ISSN 0378-5173... 

In most pharmaceutical situations, however, there is often insufficient latitude in the formula or process to allow the necessary experimentation. The pharmaceutical industry is subject to regulatory constraints that make EVOP impossible to employ in validated production processes and, therefore, impractical and expensive to use. Moreover, EVOP is not a substitute for good laboratory-scale investigation and, because of the necessarily small changes utilized, is not particularly suitable to the laboratory. In pharmaceutical development, more efficient methods are desired. 

The reader may wonder why process validation is included. This is simply a matter of consideration of the content of guidelines issued in the past that relate to development pharmaceutics. The first such pan-European guideline, adopted by the Committee for Proprietary Medicinal Products (CPMP) in 1988, included advice on both development pharmaceutics and process development. Later versions of the guidelines on development pharmaceutics and on process development have addressed these topics separately, but the historical and practical perspectives suggests that both need to be discussed here. 

Several key issues have to be addressed in the downstream processing of biopharmaceuticals regardless of the expression system. The removal of host cell proteins and nucleic acids, as well as other product- or process-related or adventitious contaminants, is laid down in the regulations and will not differ between the individual expression hosts. The identity, activity and stability of the end product has to be demonstrated regardless of the production system. The need for pharmaceutical quality assurance, validation of processes, analytical methods and cleaning procedures are essentially the same. 

A pharmaceutical company has to adopt a proactive policy of validation for its facilities, production processes, production equipment and support systems, analytical methods, and computerized systems. A properly validated approach will help to assure drug product quality, optimize the processes, and reduce manufacturing cost. 

To establish a microbial-limit testing history, all development, clinical, scale-up and process validation batches of new nonsterile dosage forms would be tested to verify that the pharmaceutical ingredients, manufacturing process, and packaging does not contribute to the bioburden of the product. After the testing history has been... 

To gain FDA approval or license for marketing, a pharmaceutical product must be shown to be safe and effective for its proposed or intended use. The drug company or sponsor must also provide evidence to show that the processes and control procedures used for synthesis, manufacture, and packaging are independently validated to ensure that the pharmaceutical product meets established standards of quality. The overall effort from the inception of a new molecular entity and the establishment of analytical, scale-up, and quality control procedures, to the collection of safety and efficacy data for consideration by the FDA as part of an NDA or BLA, is called the drug development process. 

In the case of recombinant proteins intended for use in sterile pharmaceutical products, additional process controls on microbiologic aspects of analysis must be established and validated to ensure aseptic conditions throughout the manufacturing process. 

Pharmaceutical products quality must be consistent and meet the health and regulatory requirements. The pharmaceutical industry has the obligation to validate GMP to their process to be in compliance with GMP requirements. 

This procedure provides the information required to support the sterility assurance of the drug product (product name), USP, manufactured by ABC Pharmaceutical Industries. It references the FDA Guidance titled Guidance for Industry for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Dmg Products prepared by the Sterility Technical Committee of the Chemistry Manufacturing Controls Coordinating Committee of the Center for Dmg Evaluation and Research (CDER) and the Center for Veterinary Medicine (CVM) in November of 1994. 

Validation of aseptic pharmaceutical processes is specihcally assembled in the second edition as a reference for use by managers, supervisors, and scientists in the pharmaceutical industry. The primary intent of this work is to guide design engineers, manufacturing personnel, research and development scientists, and quality control professionals in validating those processes needed for nonaseptic and aseptic pharmaceutical production. 

The purpose of the second edition is to meet the need for a ready-to-use text on the validation of aseptic pharmaceutical production and to provide general information and guidelines. It is a compilation of various theories, sterilization variables, and engineering and microbial studies that can be used independently or in combination to validate equipment and processes. The concepts and methods presented in this edition are not intended to serve as a final rule. Reciprocal methods for achieving this purpose exist and should also be reviewed and consulted, if applicable. 

Compliance Policy Guide 7132c.08. Sec. 490.100 Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval. FDA. http //www.fda.gov/ora/compliance ref/cpg/ cpgdrg/cpg490-100. html. 

U.S. Food and Drug Administration (FDA) (2004, Mar.), Sec. 490.100 Process validation requirements for drug products and active Pharmaceutical ingredients subject to premarket approval (CPG 7132c.08), FDA, Rockville, MD. 

It is clear that the aim of pharmaceutical research is to achieve zero defects and zero batch rejections, and this can be verified by process validation. One must bear in mind that exhaustive finished testing of product is not a substitute for in-process controls and process validation. 

Analytical methods validation is one of the most regulated validation processes in the pharmaceutical industry. Analytical validations are required to demonstrate that the methods employed are the most indicated for each product and that the results obtained are reliably correct. All methods employed in raw and finished product materials analysis are required to be validated. 

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