Pharmaceutical manufacture procedures

The concept of validation came up in the 1970s in association with sterilization procedures and was extended to all steps of pharmaceutical manufacturing procedures. Validation means proving that any and all procedures, processes, equipment, material, operations, and systems comply with the expected performance. Well-planned and well-conducted validation studies constitute GMP principles once they guarantee a consistently safe and efficacious final product. Validation is important for companies, first for QA, and also for cost reduction, decreasing failures, rejection, reworks, recalls, and complaints. The positive aspect of validation is an increase in productivity, as a consequence of a well-controlled process. Validation is required by the regulatory agencies of many countries. 

Process validation is the procedure that allows one to establish the critical operating parameters of a manufacturing process. Hence, the constraints imposed by the FDA as part of process control and validation of an SMB process. The total industrial SMB system, as described, is a continuous closed-loop chromatographic process, from the chromatographic to recycling unit and, with the use of numerical simulation software allows the pharmaceutical manufacturer rapidly to design and develop worst-case studies. 

EMEA Compilation of Community Procedures on Inspections and Exchange of Information - Conduct of Inspections of Pharmaceutical Manufacturers http //www.emea.europa.eu /htms/aboutus/emeaoverview.htm. 

Spedficalions regarding pharmaceutical premises, personnel and procedures must be followed by pharmaceutical manufacturers, distributors and retailers if they wish to obtain and retain their licence to operate. By means of these licences, dmg regulatory authorities control the activities of pharmaceutical manufacturers, importers and distributors and companies engaged in dmg promotion and advertising. 

There must be a safe and sanitary procedure for the disposal of sewage, trash, and other materials that could cause contamination of the building or the immediate surroundings. It should be noted that in 1967 the Pharmaceutical Manufacturers Association established sound sanitary rules and regulations for all the member firms... 

In addition to equipment, many processes/procedures undertaken during pharmaceutical manufacture are also subject to periodic validation studies. Validation of biopharmaceutical aseptic hlling procedures is amongst the most critical. The aim is to prove that the aseptic procedures devised are capable of delivering a sterile bnished product, as intended. 

Several in vitro tests are currently employed to assure drug product quality. These include purity, potency, assay, content uniformity, and dissolution specifications. For a pharmaceutical product to be consistently effective, it must meet all of its quality test criteria. When used as a QC test, the in vitro dissolution test provides information for marketing authorization. The dissolution test forms the basis for setting specifications (test, methodology, acceptance criteria) to allow batch release into the market place. Dissolution tests also provides a useful check on a number of physical characteristics, including particle size distribution, crystal form, etc., which may be influenced by the manufacturing procedure. In vitro dissolution tests and QC specifications should be based on the in vitro performance of the test batches used in in vivo studies or on suitable compendial specifications. For conventional-release products, a single-point dissolution... 

Dissolution tests are used nowadays in the pharmaceutical industry in a wide variety of applications to help identify which formulations will produce the best results in the clinic, to release products to the market, to verify batch-to-batch reproducibility, and to help identify whether changes made to formulations or their manufacturing procedure after marketing approval are likely to affect the performance in the clinic. Further, dissolution tests can sometimes be implemented to help determine whether a generic version of the medicine can be approved or not. 

According to 211.113 Control of microbiological contamination, pharmaceutical manufacturers need written procedures describing the systems designed to prevent objectionable microorganisms in both nonsterile and sterile drug products. All sterilization processes used to manufacture parenteral drugs need to be validated. 

Validation can be defined as the act of proving that any procedure, process, equipment, material, activity or system leads to the expected results . Routine and adequate validation studies form a core principle of GMP as applied to (bio)pharmaceutical manufacture, as such studies help assure the overall safety of the finished product (Box 3.1). 

In addition to equipment, many processes/procedures undertaken during pharmaceutical manufacture are also subject to periodic validation studies. Validation of biopharmaceutical... 

Understanding, modeling, and then following processes, procedures, and best practice reusable processes are essential for every business to stay at the top. The pharmaceutical manufacturing system innovation business is not exception. 

A protocol is a written set of instructions broader in scope than a SOP. SOPs are the detailed written instructions for procedures routinely performed in the course of any of the activities associated with pharmaceutical manufacturing. A protocol describes the details of a comprehensive planned study to investigate the consistent operation of new system/equipment, a new procedure, or the acceptability of a new process before it is implemented. 

The system provides a new possibility for industrial manufacturing and galenical development of pharmaceutical solids specialties and has following purposes to make possible automated, unattended production, withdrawing from scale-up experiments, and thus a shorter development time for new specialties, with the aim of a shorter time to market. Manufacturing procedures can be simplified and validated faster, and the quality of granules, tablets, and kernels compared to conunon production is equal or better. Different solids specialties have been tested and validated. 

All of the environmentally-controlled areas of pharmaceutical manufacturing and its related areas should meet the requirement of air cleanliness, which is expressed as classifications specified by official standards, such as ISO (International Organization of Standardization) or FED-STD (U.S. federal standard) 209, and/or GMP. The classification has a close relationship with the air treatment procedures and construction features. 

User requirement specifications cover more aspects than only the GMP requirement, because the URS is not written only for the validation procedure in fact, a URS is a very important project document covering technical as well as economic requirements of the technical system. Pharmaceutical manufacturing departments not only check the GMP aspects of a system additionally, following good engineering practice they will review the technical and economic aspects of a technical system. Obviously, the more experience a company gains, the more comprehensive a URS become. Past experiences such as project faults, inefficient technical systems, and bad commissioning can be included in a URS. 

The pharmaceutical manufacturer must establish effective policies and plans for regulatory compliance and validation to enable individuals to clearly understand the company commitment and requirements. Computer validation planning should ensure an appropriate training program, preparation of validation guidelines and procedures, system GMP compliance risk and criticality assessment, a documented validation strategy and rationale, clearly defined quality-related critical parameters and data for the manufacturing process. 

The regulatory authorities require the pharmaceutical manufacturer to maintain guidelines and procedures for all activities that could impact the quality, safety, identity, and purity of a pharmaceutical product. This includes procedures for implementing and supporting the validation life cycle and for process operation. 

As with all validation life-cycle documents, a validation plan is a formal document produced by the pharmaceutical manufacturer. The plan should require that all validation documentation is under a strict document control procedure, with issue and revision of documents controlled by means of an approval table, identifying the name, signature, date, and level of authority of the signatory. 

The overall project itself requires formally structured planning and control in addition to the validation plans for the computerized operation. To provide this, a project and quality plan from the pharmaceutical manufacturer (or its nominated main contractor) is normally developed as a separate and complimentary document and needs to overview all activities, resources, standards, and procedures required for the project. The plan should define project-execution procedures, quality management procedures, engineering standards, project program, and project organization (with authorities and reporting responsibilities), and reference the project validation plan. There are instances in which the project and quality plan and the project validation plan can be combined into one document. 

As part of the supply contract each supplier or subcontractor needs to provide a corresponding project and quality plan to identify and outline the procedures, standards, organization, and resources to be used to align with the requirements of the pharmaceutical manufacturer s project. The contractors and suppliers involved with GMP work should reference the project validation plan and identify the specific requirements that are to be addressed to ensure the appropriate level of documentation in support of the pharmaceutical manufacturer s validation program. 

To automate operation of pharmaceutical manufacturing processes, the computer software in many instances becomes the operating procedure, and thus the following in-built functionality and performance of the computer system itself should also be examined to ensure alignment with GMP application ... 

Any revisions that have been agreed upon by the pharmaceutical manufacturer and the selected supplier must be included in the tender package documents and quotation. Any revisions to the URS must be implemented under the pharmaceutical manufacturer s change control procedure. 

Design, development, and system build is normally a period of intense activity, in which a supplier will be involved in life-cycle activities and will need to provide a set of auditable design and development documentation to support the validation program. For this, the entire design and development process should be carried out to written and approved procedures, and all design, development, testing, and verification activities should be documented and approved in order to provide a level of computer system documentation that can be used to support the pharmaceutical manufacturer s life-cycle qualification activities. 

A test is deemed to be successful only if all the acceptance criteria defined in the test procedure have been met. A test review team should be formed that will assess and report on all tests, and any involvement by the pharmaceutical manufacturer should be documented. This team should have final authority on test findings. As required, the test review team should decide where controlled changes are required to specifications and whether or not tests should be rerun. Tests are to be conducted in a logical order, and adverse test results must be resolved before progression to any linked test or the next development phase. 

Supplier software release and replication procedures must ensure that only approved products are available for use by the pharmaceutical manufacturer. It is advisable to have release authority with review groups who are independent of the development team. 

The pharmaceutical manufacturer is not normally represented at supplier factory calibrations but for critical items should consider an option to inspect instrumentation and witness tests. Calibration certificates referencing the test procedure and test equipment should be sought, particularly for the instruments and regulating devices directly associated with quality-related critical parameter measurements and control. 

At this stage of a new installation it is possible that as-built drawings of the installation are still in a marked-up state. Marked-up drawings record the actual installation and should be submitted to the pharmaceutical manufacturer for review and approval before drawings are amended. The decision as to when to revise and reissue installation drawings can vary and will depend on the number of revisions, extent of revisions, and so on. A formal procedure is required to mark up drawings and control their use until drawings are updated and reissued. 

It should be recognized that qualification activities need to be undertaken to detailed test procedures that provide comprehensive test records, with all documentation formally reviewed and approved by a designated level of management from the pharmaceutical manufacturer. With this in mind, suitably trained qualification test personnel will be required. 

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