This Guideline was published by the Japanese Ministry of Health (English translation, may be incomplete ) Guideline on Control of Computerized Systems in Drug Manufacturing Part 1 OBJECTIVES This guideline shall govern drug manufacturing plants where "Good Manufacturing Practices for Pharmaceutical Products (MHW Ordinance No. 31, 16 Aug. 1983)" and/or "Good Manufacturing Practices for Bulk Drug Substances (PAB Notification No. 598, 15 Jul. 1988)" (hereinafter referred to as Drug GMP and other regulations) is enforced. This guideline provides the guiding principles for the development and utilization of computer system (hereinafter including all devices and equipments controlled by a computer) in process control, production control, quality control, etc. which ensures the appropriate implementation of Drug GMP and other regulations. Part 2 SCOPE OF APPLICATION This guideline shall apply to the drug manufacturing plants governed by Drug GMP and other regulations where any of the following systems are introduced. However, the system with the limited function and are operated simply by in-putting the parameters to the program fixed by the supplier of the hardware (including every device and equipment controlled by a compute) as general functions of the devices shall be exempt from this guideline. (1) The system for manufacturing process control and management including that for recording these data. (2) The system for production control such as storage and inventory of starting materials and final products including intermediates. (3) The system for documentation of manufacturing directions, testing protocols or records. (4) The system for quality control and recording of these data. Part 3 DEVELOPMENT OF THE SYSTEM 3.1 SYSTEM DESIGNING 3.1.1 Key Personnel (A) The manufacturer shall designate a manager and person/s in charge of each step of the system development ranging from "system engineering" (see 3.2) to "installation and operation test" (see 3.5). The same person may also assume the responsibility for several steps of the system development. (B) The manager shall specify individual duties of person/s in charge. 3.1.2 System Development Manual The manufacturer shall document a system development manual which shall normally include: (A) Procedures of system development (B) Documents to be prepared during each step of system development and the methods of maintaining these documents (C) Procedures for evaluation and approval of each step of system development (D) Procedures for amending or repeal of the system development manual 3.1.3 Development Schedule The manufacturer shall prepare a development schedule which in general shall describe the following: (A) Objectives of the system development (B) Time table of the system development (C) Mobilization of staff (D) Criteria for hardware selection (E) Equipment arrangement for hardware installation 3.2 SYSTEM ENGINEERING 3.2.1 The System Engineering Document The manufacturer shall prepare a system engineering document which includes, in principle, the following: (A) Composition of hardware (B) Outline of system function (C) Tabulation of input/output data (D) File composition outline (E) Countermeasures against system shutdown (F) Security control function (G) Title or name of the manager and person/s in charge 3.2.2 Approval of the System Engineering Document The manager shall ensure that the above system engineering document be prepared in accordance with the provisions of the development manual. 3.3 PROGRAM DEVELOPMENT 3.3.1 Preparation of Program Specification The manager shall ensure that the person/s in charge prepare a program specification which includes, in principle, the following: (A) Details of input/output data (B) Details of data processing (C) Title or name of the manager and person/s in charge 3.3.2 Evaluation of Program Specification and the Program (A) The manager shall ensure that the program specification be established in conformity with the system engineering document. (B) The manager shall ensure that the program is written according to the program specification. 3.3.3 Trial Test for the Program (A) The manager shall ensure that the person/s in charge prepare a trial test plan for the program including test methods and evaluation criteria of the test results. (B) The person/s in charge shall keep a record of the results of the program trial test in accordance with the provision of the trial test plan for the program. (C) The manager shall evaluate the results of the program trial test and thereafter approve it. 3.4 SYSTEM PERFORMANCE TEST 3.4.1 System Performance Test Plan The manager shall ensure that the person/s in charge prepare a system performance test (this will confirm the performance of the system such as storing the program and running satisfactorily in compliance with the designed specification in the non-production condition) plan including the following items: (A) Conditions of the system performance test (such as interface of hardware, program composition, etc.) (B) Check items of the system performance test and test data used (C) Method of the system performance test and evaluation of the test results (D) Time table of the system performance test (E) Job allocation during the system performance test 3.4.2 Implementation of the System Performance Test (A) Person/s in charge shall conduct the system performance test and maintain the test records (including system troubles observed during the test and corrective measures taken), according to the system performance test plan. (B) The manager shall evaluate the test results and approve them thereafter. The evaluation criteria of the system performance test are, in principle, as follows: a) Function (does it match the provisions of the system engineering document, etc.) b) Capability (assurance of the system response as designed in the system engineering document, etc.) c) Reliability (does recovery function work satisfactorily, etc.) d) Operation (appropriateness of the operation of terminal devices, etc.) 3.5 INSTALLATION AND OPERATION TEST 3.5.1 Installation Plan The manager shall ensure that the person/s in charge prepare installation plan including, in principle, the following: (A) Place of installation (B) Time table of installation (C) Environment requirements recommended by the hardware supplier, such as temperature, humidity, vibration, etc. (D) Installation conditions such as power source, ground, etc. (E) Title or name of the manager and person/s in charge 3.5.2 Installation of Hardware (A) The person/s in charge shall install the hardware, ensure that it is appropriately installed and keep a record in accordance with the installation plan. (B) The manager shall evaluate the above and approve it thereafter. 3.5.3 Operation Test Plan The manager shall ensure that the person/s in charge prepare an operation test (which shall thereafter mean every test for the evaluation of production and control performance under practical production conditions according to the specifications) plan, which shall include the following: (A) Examination method for the function and capability of the system under operation (B) Analysis and evaluation method for the test 3.5.4 Implementation of the Operation Test (A) The person/s in charge shall conduct the operation test in accordance with the provisions of the operation test plan and keep a record of the test results. (B) The manager shall evaluate the test results and thereafter approve it. 3.6 OTHERS All or part of the activities described in "development of the system" (see part 3) can be entrusted to other firms on condition that the manufacturer concerned shall obtain and maintain the relevant documents of the activities from the contracting firm or otherwise ensure that these documents are properly retained by the contracting firm. However, the contracted activities which fall within "system performance test" (see 3.4) or "installation and operation test" (see 3.5) shall be directly supervised, evaluated, and accordingly approved by the responsible person designated by the manufacturer concerned. Part 4 OPERATION CONTROL 4.1 GENERAL 4.1.1 Responsibility of Operation (A) The manufacturer shall designate a manager and person/s in charge for each of the operation step prescribed in this part from "operation of hardware" (see 4.2) to "self inspection" (see 4.6). The same person may also assume responsibility for several steps. (B) The manager shall specify the duties of the person/s in charge. 4.1.2 Operation Procedures The manufacturer shall prepare an operation procedure including, in principle, the items shown below: (A) Operation of the hardware a) Standard operation procedures of the hardware b) Education and training of personnel (B) Inspection and maintenance a) Periodical maintenance i) Confirmation of appropriate program use ii) Confirmation of system performance satisfying the function and capability as described in the specifications iii) Necessary calibration of measuring instruments b) Daily inspection i) Maintenance of the environment of the operation room ii) Inspections before and after operation iii) Inspection of in-putted data c) Inspections to be carried out by specialists (C) Countermeasures against accidents a) Alarm setting of the system b) System halt conditions c) Personnel organization in case o f accidents i) Organization chart ii) Reporting system to the manager d) Recovery procedures e) Procedures for cause finding studies f) Procedures for the prevention of future accidents g) Evaluation of the possible effects of the accidents or troubles of the system to the products h) Procedures and check items for the resumption of operation after system shutdown i) Procedures for necessary manual back-up system i) Scope of manually controlled devices ii) Criteria to transfer to manual system iii) Evaluation of proper performance of manual system (including confirmation of relationship between both systems) iv) Training for back-up manual system (D) Security control a) Restriction to the hardware area b) Designation of the person/s who are allowed to enter, modify or delete data, and prevention of unauthorized data access c) Control of passwords and identification codes i) Registration, change and deletion procedures of passwords/identification code ii) unauthorized opening of passwords/identification codes iii) Security measures in case of changes of personnel authorized to use passwords/identification codes d) Programs and a set of data to be copied on a back-up system, as well as provisions on the frequency of the renewal of the back-up copies and storage condition e) Scope of activities of person/s in charge E) Title or name of the manager and person/s in charge of each step 4.1.3 System Alteration (A) The manufacturer shall prepare a system alteration standard code which includes, in principle, the following: a) Procedures for alteration application and approval of alteration b) Examination after system alteration c) Amendment of operation procedures d) Notification of the amended parts to the persons concerned e) Title or name of the manager and person/s in charge (B) The provisions ranging from "system engineering" (see 3.2) to "installation and operation test" (see 3.5) of part 3 "development of the system" shall generally apply to the system alteration when associated with program change after its introduction. 4.2 OPERATION OF HARDWARE 4.2.1 The manager shall ensure that person/s in charge operate the hardware in accordance with the standard operation procedures provided in the operation procedures. 4.2.2 The manager shall train the person/s in charge based on operation procedures. 4.3 INSPECTION AND MAINTENANCE 4.3.1 The person/s in charge shall implement inspection/maintenance in line with the provision of operation procedures and keep a record of this. 4.3.2 The manager shall ensure that inspection/maintenance be properly undertaken based on the inspection/maintenance records. 4.4 ACCIDENTS 4.4.1 The manager shall ensure that the person/s in charge take immediate actions when accidents occur in the system in accordance with the provisions of the operation procedures and let him/her conduct a cause finding study as well as take necessary actions for the prevention of these accidents. 4.4.2 Resumption of operation may be allowed after the accidents on condition that the recovery is assured by the manager according to operation procedures. 4.4.3 The manager shall have the following records to be maintained by person/s in charge: (A) Contents and results of the accident (B) Records of cause finding study and preventive measures (C) Confirmation by the manager 4.4.4 The manager shall ensure that manual back-up system be appropriately operated at the time of the accident in accordance with the operation procedures. 4.5 SECURITY CONTROL 4.5.1 The manager shall take necessary steps to prevent unauthorized persons from entering the computer area, in accordance with the operation procedures. 4.5.2 The manager should prevent unauthorized data access through designation of qualified person/s allowed to process data by in-putting, modifying, deleting, etc. according to the operation procedures. 4.5.3 The manager shall assume security control for passwords and identification codes in line with the operation procedures. 4.5.4 The person/s in charge shall provide a back-up copy of the system and separately retain this in accordance with the provision of the operation procedures. 4.6 SELF INSPECTION 4.6.1 The manufacturer shall ensure that the operation of the system is consonant with this guideline through periodical inspection by its manager. 4.6.2 The manager shall maintain a record of the self inspection. Part 5 DOCUMENTATION (including plan, procedures and others) The manager shall retain the relevant documents and records prepared according to this guideline in the following manner: 5.1 METHODS The following methods may be adopted: (A) Paper print-outs (B) Magnetic tape or other methods. When this applied, the following points shall be taken into account. a) A back-up copy shall be produced for documents and records. b) Production and amendment of the documents and records shall be properly checked or recorded by the manager. 5.2 STORAGE PLACE Documents and records relevant to the development stage shall be maintained in each manufacturing premises concerned. All the documents may, however, be retained collectively in the major premise of the firm and copies concerned be distributed to each manufacturing premises. 5.3 STORAGE PERIOD (A) Documents and records relevant to the system development stage shall be retained for three years from the date of repeal of the operation of the system concerned (or, for one year after the expiry date in case of a drug required for labelling of the expiry date). (B) Records relevant to system operation shall be retained for three years from the date of recording (or, for one year after the expiry date incase of a drug required for labeling of the expiry date). Part 6 DATE OF ENFORCEMENT This guideline shall be enforced on 1 April 1993. The system already developed or under development on this date shall be exempted from this guideline. c:\data\wp\rory\mfgguide 10