Tài liệu Pharmaceutical Coating Technology (Part 11) ppt

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 comp

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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.’

• 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;

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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

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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:

• Description of required protocols

• Lists of standard operating procedures (SOPs)

• Required document matrices

• Validation schedules/construction schedule/integrated schedule

• Preventive maintenance programme

• Change control programme

• Document control programme

• Manpower requirements

• Key personnel

• Protocol examples

• SOP examples

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Fig 11.1 Schedule for validation of coating processes from Cole, G.C (1990)

Pharmaceutical Production Facilities: design and applications, Ellis Horwood

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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)

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

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

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

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

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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

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

Page 275might be: Pressure at 5.2 lb in2(g), temperature at 37±0.5°C, flow rate at 10±1.0 GPM, pH at 7.0±0.2

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 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

Retrospective validation:

Validation of a process for a product already in distribution based upon establishing documented

evidence, through review/analysis of historical manufacturing and product testing data, to verify that a specific process can be consistently produced meeting its predetermined specifications and quality

attributes In some cases a product may have been on the market without sufficient premarket process validation Retrospective validation can also be useful to augment initial premarket prospective

validation for new products or changed processes

Revalidation:

Repetition of the validation process or a specific portion of it

Specifications:

Document which defines what something is by quantitatively measured values Specifications are used

to define raw materials, in-process materials, products, equipment and systems

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Standard operating procedure (SOP):

Written procedures followed by trained operators to perform a step, operation, process, compounding or other discrete function in the manufacture or production of a bulk pharmaceutical chemical, biological,

or drug product

Utilities/systems:

Utilities/systems are buildings, mechanical equipment and include such things as heating, ventilation and air conditioning (HVAC) systems, process water, product water (purified water, USP), water for injection (WFI), clean steam, process air, vacuum, gases, etc They include electromechanical or

computer-assisted instruments, controls, monitors, recorders, alarms, displays, interlocks, etc., which are associated with them

Validation protocols are written plans stating how validation will be conducted, including test

parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results This definition is provided by the FDA of the USA A maximum of four

protocols are possible They are protocols for installation qualification, operation qualification, process validation and product validation When the protocols have been executed successfully they produce documented evidence that the system has been validated

Validation scope:

The scope answers the question: What is to be validated? In the instance of the manufacturing plant, this would include the elements which impact critically on the quality of the product The elements which require validation are facilities, utilities/systems, process equipment, process and product Worst case: A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of a process or product failure when compared to ideal conditions Such conditions do not necessarily induce product or process

11.4.1 Manufacture of the core

This should detail the following:

• formulation;

• list of ingredients and their specifications;

• equipment required for manufacture, e.g mixer, granulators, driers, compressing equipment, etc.,