Tài liệu Pharmaceutical Coating Technology (Part 11) ppt

Page 267 11 Validation of tablet coating processes Graham C.Cole SUMMARY Validation is a concept that means different things to different people. This chapter will highlight all the activities that are necessary to ensure that all aspects of the coating process are fully documented from design through to operation, to provide compliance with regulatory requirements. ‘If it hasn’t been documented, it hasn’t been done.’ FDA 11.1 INTRODUCTION The FDA defines validation as: ‘Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.’ Validation has also been defined as the activity performed to demonstrate that a given utility, system, process or piece of equipment does what it purports to do. The primary means of accomplishing this end is the scientific study designed to specifically permit the determination as to whether the entity under scrutiny in fact: • meets or exceeds the specifications of its design; • is properly built, shipped, received, stored, installed, operated and maintained; • is suitable for its intended application; • is in accordance with principles established and generally accepted by the scientific community; • conforms to basic cGMP design criteria; Page 268 The EC has adopted very similar cGMP criteria. This scientific study is generally detailed in a validation protocol. A well-designed validation programme properly supported by senior management will accrue considerable benefit to its sponsor. Not only will regulatory obligations be fulfilled, but also processes will be optimized, productivity improved and downtime reduced. In short, a validation programme with a sound scientific base and proper experimental design is simply good business if taken seriously and executed conscientiously. Among the most relevant of the regulatory issues from the Code of Federal Regulations, Volume 21, that should be considered in the assembly of any validation programme are the following: It is also necessary to take into consideration the various guidelines and manuals published by the EC, FDA, NIH and OSHA, e.g. The Rules Governing Medicinal Products in the European Community. Vol. 4: Guide to Good Manufacturing Practice for Medicinal Products, 1989. GMP regulations state what must be done, but do not attempt to explain how to do it; Guides and Guidelines do that. Since GMPs represent substantive law, they can be established only by due process. FDA Guides and Guidelines, on the other hand, can be written and made effective at any time, with or without public notice or hearings; but, they are not legally binding on the industry. In the USA, a person, a pharmaceutical firm, or the whole industry, can write its own guidelines if it so elects. Obviously a compliance guideline is not very valuable unless all parties involved are in general agreement. Consequently, with regard to validation in the US, the last 13 years have seen a remarkably cooperative and widespread effort by members of the regulatory sector, the industrial sector, academia and, most recently, even the vendor sector, to establish meaningful guidelines. 11.2 SCOPE The validation requirements are identified in the Documentation Master Plan for a facility. This Plan is considered necessary to explain all the constituent parts that are listed in the introduction and provide all the validation team members with a ‘bible’ so that they all ‘sing from the same hymn book’. The Master Plan explains the GMP type documentation required and has the effect of producing similarity/ uniformity of documentation. • will satisfy the concerns of regulatory bodies; • is capable of consistently producing a product that is fit for use; • will meet objectives established for productivity, safety and quality. Part 58 Good Laboratory Practice For Non-clinical Laboratory Studies. Part 210 Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General. Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals. Page 269 11.3 MASTER PLAN The Master Plan serves a dual purpose: As part of the ‘Validation Schedules’ portion of the Master Plan, the typical schedule outline in Fig. 11.1 should be developed to show a completion date depending on the company’ s specific requirements. It is a living schedule and will evolve with time. At this stage it is necessary to highlight some of the areas that should be addressed in the validation programme, even though the process under consideration is tablet coating. All validation programmes have common features and these are addressed under the following headings in the Master Plan. 1. It is a document which may be presented to regulatory bodies to convey the level or understanding of the company responsibilities concerning the validation programme along with plans to discharge that responsibility. 2. It is a guide to those administering and performing validation activities. The Master Plan will address and include, but need not necessarily be limited to, the following topics: • Approvals. • Introduction. • Scope. • Glossary of terms. • Preliminary drawings/facility design. • Process descriptions. • Rooms and room classifications. • Description of utilities. • Description of process equipment. • Automated systems. • Equipment history files. • Construction documentation. • Description of required protocols. • Lists of standard operating procedures (SOPs). • Required document matrices. • Validation schedules/construction schedule/integrated schedule. • Protocol outlines/summaries. • Environmental monitoring. • Analytical testing procedures. • Calibration programme. • Training programme. • Preventive maintenance programme. • Change control programme. • Document control programme. • Manpower requirements. • Key personnel. • Protocol examples. • SOP examples. Page 270 Fig. 11.1 Schedule for validation of coating processes from Cole, G.C. (1990) Pharmaceutical Production Facilities: design and applications, Ellis Horwood. Page 271 Page 272 Approvals The approval of this Validation Master Plan will be the joint responsibility of a number of functional areas in the company’s facility. Examples: The completion of this stage indicates review of the contents by the relevant disciplines and approval by responsible individuals. Glossary of terms This is not an exhaustive list but highlights some of the terms relevant to coating processes that must must be defined. Acceptance criteria: The product specifications and acceptance/rejection criteria, such as acceptable quality level and unacceptable quality level, with an associated sampling plan, that are necessary for making a decision to accept or reject a lot or batch (or any other convenient subgroups of manufactured lots). Action levels: Levels or ranges which, when deviated from, signal a potential drift from normal operating conditions; these ranges are not perceived as being detrimental to end-product quality. Audit: An audit is a formal review of a product, manufacturing process, equipment, facilities or systems for conformance with regulations and quality standards. Calibration: Comparison of a measurement standard or instrument of known accuracy with another standard or instrument to detect, correlate, report, or eliminate by adjustment any variation in the accuracy of the item being compared. Certification: Documented statement by qualified authorities that a validation event has been done appropriately and that the results are acceptable. Certification is also used to denote the acceptance of the entire coating operation and the manufacturing facility where it takes place, as validated. Change control: A formal monitoring system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect validated status and take preventive or corrective action to ensure that the system retains its validated state of control. • Manufacturing. • Engineering. • Quality Assurance. • R&D. • Safety. • Site Manager. • Regulatory Affairs. • Validation Manager. Computer validation: This is particularly relevant to automated coating systems. The validation of computers has been given a particular focus by the FDA. Three documents have been published for agency and industry guidance. In February 1983 the agency published the Guide to Inspection of Computerized Systems in Drug Processing; in April 1987, the Technical Reference in Software Development Activities was published; on 16 April 1987 the agency published Page 273 Compliance Policy Guide 7132 in Computerized Drug Processing: Source Codes for Process Control Application Programmes. In the inspection guide, attention is called both to hardware and software; some key points being the quality of the location of the hardware unit as to extremes of environment, distances between CPU and peripheral devices, and proximity of input devices to the process being controlled; quality of signal conversion, e.g. a signal converter may be sending inappropriate signals to a CPU; the need systematically to calibrate and check for accuracy of I/O devices; the appropriateness and compatibility within the distributed system of command overrides (e.g. can an override in one computer controlled process inadvertently alter the cycle of another process within the distributed system?). Maintenance procedures form another matter which interests the agency during an inspection. Other matters of concern are methods by which unauthorized programme changes are prevented, as inadvertent erasures, as well as methods of physical security. Hardware validation should include verification that the programme matches the assigned operational function. For example, the recording of multiple lot numbers of each component may not be within the programme, thus second or third lot numbers of one component may not be recorded. The hardware validation should also include worse case conditions, e.g. the maximum number of alphanumeric code spaces should be long enough to accommodate the longest lot numbering system to be encountered. Software validation must be thoroughly documented—they should include the testing protocol, results, and persons resonsible for reviewing and approving the validation. The FDA regards source code—i.e. the human readable form of the programme written in its original programming language, and its supporting documentation for application programmes used in any drug process control—to be part of the master production and control records within the meaning of 21CFR, Parts 210, 211 (Current Good Manufacturing Practice Regulations). As part of all validation efforts, conditions for revalidations are a requirement. Concurrent validation: Establishing documented evidence that the process, which is being implemented, can consistently produce a product meeting its predetermined specifications and quality attributes. This phase of validation activities typically involves careful monitoring/recording of the process parameters and extensive sampling/testing of the in-process and finished product during the initial implementation of the process. Critical process variables: Those process variables that are deemed important to the quality of the product being produced. Drug product: A finished dosage form—for example, coated tablet, capsule, solution, etc., —that contains an active drug ingredient generally, but not necessarily, in association with inactive ingredients. The term also includes a finished dosage form that does not contain an active ingredient but is intended to be used as a placebo. Dynamic attributes: These are classified into functional, operational and quality attributes (see below). EC: European Community. Page 274 Edge of failure: A control or operating parameter value that, if exceeded, may have adverse effects on the state of control of the process and/or on the quality of the product. Facilities: Facilities are areas, rooms, spaces, such as receiving/shipping, quarantine, rejected materials, approved materials warehouse, staging areas, process areas such as coating make-up and finishing rooms, etc. FDA: Food and Drug Administration of the USA. Functional attributes: Functional attributes are such criteria as controls, instruments, interlocks, indicators, monitors, etc., that are operating properly, pointing in the correct direction, valves which permit flow in correct sequence, etc. Good Manufacturing Practices (GMPs): The minimum requirements by law for the manufacture, processing, packaging, holding or distribution of a material as established in Title 21 of the Code of Federal Regulations, Part 211 for finished pharamceuticals. Installation qualification protocol: An installation qualification protocol (IQ) contains the documented plans and details of procedures which are intended to verify specific static attributes of a facility, utility/system, or process equipment. Installation qualification (IQ), when executed, is also a documented verification that all key aspects of the installation adhere to the approved design intentions and that the manufacturer’s recommendations are suitably considered. Operational attributes: Operational attributes are such criteria as a utility/system’s capability to operate at rated ranges, capacities, intensities, such as revolutions per minute, spray rate per minute, kilos per square centimetre, pounds per square inch, temperature range, etc. Operation qualification protocol: A operation qualification protocol (OQ) contains the plan and details of procedures to verify specific dynamic attributes of a utility system (air supply to coating pan) or process equipment (coating pan) throughout its operating range, including worse case conditions. Operation qualification (OQ), when executed, is documented verification that the system or subsystem performs as intended throughout all anticipated operating ranges. Processes: Processes are those activities which are repeated frequently such as: spray coating; preparation of coating solutions (suspensions); pH adjustment, including the preparation of solutions which are used for adjusting the pH; cleaning in place (CIP), and the preparation of CIP solutions; the various piping adjustments required to direct the coating solutions, sanitizing/sterilizing in place (SIP) and supportive activities; any sterilization of product, component, garment, equipment, etc.; and any electromechanical or computer-assisted processes associated with them. Process equipment: Process equipment are such items as scales, load cells, flow meters, coating pans, mixers, reaction/process/storage vessels, centrifuges, filters, driers, packaging equipment including electromechanical or computer-assisted instruments, controls, monitors, recorders, alarms, displays, interlocks, etc., which are used in the manufacture of pharmaceutical products. Process parameters: Process parameters are the properties or features that can be assigned values that are used as control levels or operating limits. Process parameters ensure the product meets the desired specifications and quality. Examples [...]... for raw materials, in-process testing and finished product testing 11.4.2 Tablet -coating process This should detail the following: • formulation • list of ingredients and their specifications • equipment required for the coating process, e.g coating solution or suspension, preparation vessels, mills, mixers, homogenizers, coating pans, spray-guns • service requirements such as compressed air, purified... PV must cover for compressed air, used in a coating pan and for the coating process Compressed air is the utility service selected as it is a product contact material, i.e it is used in the spraying operation The coating pan listed in Table 11.1 will have several parts: 1 2 3 4 5 6 the pan; the spraying equipment; the unit that holds, mixes, and pumps the coating solution to the spray-guns; the autowash... process parameters Two aspects of this part of the validation development programme are critical Side-vented coating pans can have poor mixing characteristics, and if the coating on a tablet is designed to provide part of a sustained release profile, then all the tablets must have the required amount of coating applied to them This may well mean experimentation with different types of baffles and speeds to... contained in the protocol has been entered in advance by the validation team Page 280 Fig 11.3 Systems architecture from Cole, G.C (1990) Pharmaceutical Production Facilities: design and applications, Ellis Horwood Page 281 Fig 11.4 Data flow diagram from Cole, G.C (1990) Pharmaceutical Production Facilities: design and applications, Ellis Horwood Page 282 Table 11.1 Protocol requirements for utilities,... not necessarily induce product or process failure So, what is required to develop the documentation for validation of the coating process? 11.4 PROCESS DESCRIPTION Initially we need the process description This can be divided into two parts: the manufacture of the core and the coating process 11.4.1 Manufacture of the core This should detail the following: • formulation; • list of ingredients and their... equipment; the unit that holds, mixes, and pumps the coating solution to the spray-guns; the autowash system, if fitted; the system used to monitor and record the amount of coating applied; the air-handling system The main item is the coating pan and the development of protocols will follow the same pattern as for the compressed air It is necessary to define the materials of Page 284 Table 11.2 Protocol... assurance that a specific coating process will consistently produce a product meeting its predetermined specifications and quality attributes Process validation protocol: Process validation protocol (PV) is a documented plan and details of procedures to verify specific capabilities of process equipment system through the use of simulation materials, such as the use of placebo tablets in a coating process, a... use of simulation materials, such as the use of placebo tablets in a coating process, a nutrient broth in the validation of an aseptic filling process, or the use of a placebo formulation in a tablet coating process Here the term process validation (PV) will be used to include the use of the product as the material to validate the process Product validation: A product is considered validated after... Process steam X X X Process control and monitoring computer system X X X Clean-in-place X X X Powder mixers X X — Granulators X X — Mills/sieving equipment X X — Dryers X X — Compressing equipment X X — Coating pans X X — Liquid mixing equipment X X — Product process X X X Facility Utilities Systems Processes The physical validation begins with the execution of the installation qualifications for the... been concluded This same pattern follows all the remaining entities in the order: utilities, systems and processes, as enumerated in Table 11.1 11.7 STANDARD OPERATING PROCEDURE (SOP) DEVELOPMENT All pharmaceutical facilities and their operations require SOPs to be in place to comply with the regulations All new processes require SOPs to be written that cover a number of essential operating areas • . equipment required for the coating process, e.g. coating solution or suspension, preparation vessels, mills, mixers, homogenizers, coating pans, spray - guns. specific dynamic attributes of a utility system (air supply to coating pan) or process equipment (coating pan) throughout its operating range, including worse