The Good Manufacturing Practice For Pharmaceutical Products In Korea(kgmp) 414b4t

THE GOOD MANUFACTURING PRACTICE FOR PHARMACEUTICAL PRODUCTS IN KOREA(KGMP)

issued 2008.01.15

Ministry of Health and Social Affairs Korea Pharmaceutical Manufacturers Association

1. Definition of Definition given below applies to the as used in these standards. 1) “Control number” means numbers given to materials and etc. which is not applicable for manufacturing unit in order to control them and it can be numbers, texts or combination of numbers and texts. 2) “Calibration” means to demonstrate that a measuring instrument, testing instruments or recording device produces results within allowable margin of error by comparison with those produced by a reference and to adjust the instrument or device to produce results within the margin if it produces results out of the margin. 3) “Deviation” means actions which departure from an established standard during a process of production or quality control. 4) “Out-of-specification (OOS)” means that a test result is out of an established specification of the test. 5) “Aseptic area” means work areas where aseptic material or sterilized containers are exposed to the air and areas where filling or sealing of sterile products is conducted. And it includes area where aseptic operations as aseptic test are conducted. 6) “Intermediate product” means the product in the processes, which must undergo further the necessary process before it becomes a finished product. 7) “Validation” means the verification and documentation that a specific process, method, mechanical instrument or system will consistently produce a result meeting pre-determined acceptance criteria. 8) “Yield” means the percentage of actual production quantity on the theoretical production quantity. 9) “Yield control criteria” means a range of mean production yield of each product when manufacturing procedures were carried out normally. 10) “Actual production quantity” means actual quantity which was yielded from a manufacturing procedure. 11) “Finished drug product” means a drug product in a certain pharmaceutical form which has undergone all stages of production and is finally going to be istered to human body. 12) “Finished product” means a finished drug product or a drug substance which has undergone all stages of production. 13) “Raw material” means any substance used in the production of a finished product including those that might not be present in the finished product. (Packing materials are excluded). 14) “Drug substance” means a substance which was manufactured through synthesis, fermentation, extraction or combination of these steps and used in the production of a finished drug product.

15) “Material” means a raw material or a packing material. 16) “Theoretical yield” means quantity of an intermediate product or a finished product that is theoretically calculated based upon input amount of drug substances. 17) “Packaging material” means any material used for packaging and labeling, including container. 18) “Reprocessing” means to repeat parts of pre-determined manufacturing steps for an intermediate product which deviates from the standard. 19) “Acceptance evaluation” means to and document that machineries and facilities are manufactured and installed as designed and work as and d 20) “Production” means all operations involved in the production of a medicinal product including packaging and labeling. 21) “Batch” or “Lot” means a defined quantity of the drug manufactured in the same process so that it could be expressed to be homogeneous 22) “Batch number” or “Lot number” means the number, letter or their combination given per the batch or the lot so as to identify all the complete history of the production control and distribution. 23) Major process or major machinery or equipment 24) “Clean area” means an area with defined environment control of introduction of particulates and microbial contamination to maintain them under a certain degree. 25) “Cleanliness grade” is a controlled level of cleanliness of clean area to be maintained.

2. Premise Maintenance & Environment Control 2.1. Premise Maintenance A manufacturer of pharmaceuticals should make the concerned manufactory suitable to the standards ordained by the Facilities Standard Mandate for Pharmacy, Manufacture, Importer and Dealer of Drugs, and maintain the manufactory properly by regular checks according to the provisions of the following items so as to have no trouble in the production and quality control. 1) Machines or equipment of a work place should be laid out in a order corresponding to the sequence of the operations. 2) Major machines or equipment for manufacturing should be labeled with numbers or codes to be distinguished from each other and product name, batch number and the date of use should be recorded when the machines or equipment were used. 3) Required amount and quality of water used in the manufacture should be secured.

4) Pipework should be clearly labelled to indicate the contents and the direction of flow. 5) It should be controlled that lubricants, coolants or etc do not affect the quality of drug product. 6) Sewer in workplace should be designed to avoid reflux and be sterilized on a regular basis. 7) Machines or equipment which are not used due to out of order and etc., should be removed from production areas, or be clearly labeled as defective. 8) Qualification evaluation should be performed for major machinery and equipment which are used for non-sterile drug product except herbal medicines or drugs for clinical trials. 2.2. Control of Automated System 1) If automated equipment (including computerized system) for manufacturing and quality control are used the systems should be regularly calibrated and the functions should be checked up and recorded on a regular basis. 2) Records of automated equipment should be changed only by an authorized person and be controlled properly. 3) All the data related to automated equipment should be stored and kept separately. In this case the data should be stored using alternate systems such as print-outs, tapes or microfilms so that the data which is separately kept is not to be lost. 2.3. Environment Control A manufacturer should maintain the proper operation environment in the concerned manufactory according to the provisions of the following items so as to prevent the contamination in the process and record the process. 1) Clean area and grade of cleanliness for workspace should be established in accordance with the kinds, the dosage forms, the production methods and the production facilities of drugs and it should be periodically checked and control to maintain the cleanliness grade. 2) The air-handling unit should be checked periodically and grade of cleanliness and difference of pressure between workplaces should be maintained. 3) Regular check-ups should be conducted to maintain appropriate temperature and humidity for manufacturing condition and storage condition.

3. Organization 3.1. Structure of organization 1) A manufacturer should establish the departments of production and of quality control independently each other, and appoint personnel to the manager of production department and of quality control department differently. However at the contract manufacturer or the sub divider the same person may be allowed. 2) The responsible person of item 1) should be a production manager according to Article 36 of Pharmaceutical Law and have sufficient knowledge about these standards ("KGMP" as follows). 3) The manufacturer should have an adequate number of personnel to perform tasks for manufacturing control and quality control and the workmen should be educated and trained for KGMP and their tasks. 3.2. The Manager of Production Department The manager of production department is responsible for the in-process control, the production hygiene control and the storage control and should carry out the following particulars: 1) To approve by g his/her name, preserve and maintain the master formula, production control standards and production hygiene control standards in order to carry out the production control appropriately 2) To order production processes according to manufacturing instructions of item 4.1. 15) and to check if the production is carried out based on the manufacturing instructions. To investigate and record if there is deviation for drug products except ones for clinical use 3) To check and confirm whether or not production hygiene control and storage control are conducted according to standards 4) To conduct and check qualification evaluation for major machinery and equipment which are used for non-sterile drug product except herbal medicines or drugs for clinical trials. 3.3. The Manager of Quality Control Department The manager of quality control department who is responsible for the quality control of raw materials, intermediate products and finished products should carry out the following particulars: 1) To approve by g his/her name, preserve and maintain the master formula and the quality control standards so as to carry out the quality control appropriately. 2) To order test according to the test instructions of item 4.2. 1) and to check if the test is carried out based on the test instructions. To investigate and record if there is deviation or out-of-specification obtained for drug products except ones for clinical use 3) To review and approve all the documents and processes related to quality

4) To approve and supervise particulars of 2.3. Environment Control 5) To approve and supervise particulars of 6. Validation for non-sterile drug product except herbal medicine or ones for clinical use, however, the quality manager doesn’t need to do this where a validation manager is appointed 6) To conduct stability test 7) To conduct annual quality evaluation for non-sterile drug product except herbal medicine or ones for clinical use 8) To review a manufacturing record by each lot and a certificate of analysis and authorize to release a product 9) To decide whether or not to use raw material, whether or not to proceed to a manufacturing process or whether or not to release products based on test results and to notify the results to related departments according to pre-arranged procedure 10) To check whether or not the rejected material is handled according to specified procedure 11) To supervise particulars of handling of product complaints and product recall 12) To approve change control management 13) To plan and conduct self-inspections 14) To evaluate contract manufacturers and test facilities and manufacturers of raw material but for drugs for clinical use 15) To appoint storage control manager for drug substance, packing material and finished product 3.4. Committee Rules for a committee should be established including the following particulars and a committee should be organized and maintained to set up and revise all kinds of standards and to run those standards smoothly. 1) Purpose of a committee 2) Organization (including chief, and secretary of the committee) and responsibilities. Subcommittees for each field if necessary 3) Conference management 4. Standards

For ensuring proper performance of the production control and the quality control, the manufacturer should prepare and maintain Master Formula, Quality Control Standards, Production Control Standards and Production Hygiene Control Standards. 4.1. Master Formula The Master Formula should be prepared for each product and include the following items; 1) Product name, pharmaceutical form and description of the product 2) Date of registration or date of change of ed information 3) Indication, posology and precautions for use 4) ed quantitative composition and standard amount for batch. Adjustments of standard amount if necessary 5) Manufacturing flow chart and detailed manufacturing methods and test methods for each procedure (where a certain range of the manufacturing process is done by a contract manufacturer the range should be stated in the Master Formula) 6) Theoretical yield per step of the processes and yield control criteria 7) Cautions for operations 8) Specifications and analytical methods of raw materials, intermediate and finished product. (Separate specifications and analytical methods should be established for raw materials which is possible to be mixed with foreign matters or insects or to be contaminated by microorganisms) 9) Facilities and equipment required for production and quality control 10) Storage condition 11) Expiry date 12) Record of history 13) Production instructions including the following particulars; ① Identification number of the production instructions ② Product name, pharmaceutical form and description ③ Batch number, date of manufacture and expiry date ④ Batch size

⑤ Test number of raw material used in the production, ed quantitative composition and standard amount for the batch size ⑥ Detailed manufacturing instructions and cautions for operations ⑦ Yield control criteria per manufacturing process ⑧ A person who ordered to manufacture and the date when the order was given 14) Others, if needed 4.2. The Quality Control Standards The Quality Control Standards should include the following particulars: 1) Test instructions including the following particulars; ① Product name, batch number or control number, date of manufacture ② Identification number of the test order, a person who gave the order and date when the order was given ③ Test items and specifications 2) A person who did sampling, the amount of sample, the place where the sample was taken, the method of sampling, cautions for sampling (such as sterility) and precautions to be observed to avoid contamination of the material 3) Procedure for notifying test results to relevant departments 4) Check-ups for test facilities and apparatuses 5) Stability test 6) Control of storing samples of drug substances and finished products 7) Control of reference materials and reagents 8) Procedure for dispatching samples to a contractor and for judging the test results where a certain part of procedures are done by a contract manufacturers or test facilities 9) Other required details related to responsibilities specified in Item 3.3. The Manager of Quality Control Department 4.3. Production Control Standards The Production Control Standards should include the following particulars. 1) Particulars related to Production procedure control

① Entry restrictions to the workplace ② Process examination methods. Especially methods of double check-ups for major processes such as weighing input of raw material, sterilization and etc. ③Methods to decide whether raw materials being used for the production is appropriate or not ④ Methods of reprocessing 2) Particulars related to control of facilities and equipment ① Methods of regular check-ups ② Methods to label in-use facilities and equipment ③ Actions to be taken in case of accidents such as disorder of facilities or equipment ④ Methods of setting standards or calibration of measuring devices ⑤ Methods of qualification evaluation for major machinery and equipment which are used for nonsterile drug product except herbal medicines or drugs for clinical trials. 3) Particulars related to the control of raw materials: ① Methods to check product name, specifications, quantity and defects of a container. Methods to handle material in a defected container ② Place and method of storage ③ Procedures for handling the rejected materials ④ Measures for preventing mixing-up or cross-contamination in handling ⑤ Method of first in, first out and labels of weighed container ⑥ Stock control ⑦ In-house specifications (including method of quality assurance) and retest methods where is possible concern of quality, such as exposed to the air during long term storage 4) Particulars related to the control of packaging materials: ① Methods to check product name, specifications, quantity and defects in packaging. Methods to handle when there is defect in packaging ② Place and method of storage ③ Procedures for handling the rejected materials

④ Method of reject and method of checking the quantity of the returned labeling materials unused ⑤ Actions to be taken in changing the description of labels ⑥ Measures for preventing mixing-up or cross-contamination in handling ⑦ Stock control ⑧ In-house specifications (including method of quality assurance) and retest methods where is possible concern of quality, such as exposed to the air during long term storage 5) Particulars related to the control of finished product: ① Method of checking the approval on the release for distribution and warehousing. ② Place and method of storage ③ First in, first out at releasing 6) Particulars related to the production control of the contract manufacture: ① Methods for supplying raw material and methods for carrying and storing intermediate or finished products ② Methods of evaluating the production records of the contract acceptor. 7) Other required details related to responsibilities specified in Item 3.2. The Manager of Production Control Department 4.4. Production Hygiene Control Standards The production Hygiene Control Standards should include the following particulars: 1) Methods of checking and taking actions for workman’s health management and health condition 2) Particulars regarding hygiene such as methods of how to wash hands for workmen, sterilization methods and etc. 3) Specifications of a working uniform, how to launder it and how to wear it 4) Methods to clean a work place (including sterilization if necessary) and period of cleaning 5) Reagents and equipment used for cleaning a work place 6) Details about control of grade of cleanliness 7) Cleaning and evaluation of manufacturing facilities ① Appointing a responsible person

② Schedules of cleaning and washing ③ Cleaning methods including reagents and tools used for cleaning ④ Instructions for disassembling and reassembling each article of manufacturing equipment ⑤ Instructions for the removal of previous batch identification ⑥ Instructions for the protection of clean equipment from contamination prior to use ⑦ Inspection of equipment for cleanliness immediately before use 8) Instructions for protection from insects and rodents and cleaning period 9) Other required details related to responsibilities specified in Item 3.2. The Manager of Production Control Department 5. Documentation 5.1. Document creation 1) Document management standards should be prepared including all the details regarding document issuance, revision, approval, distribution, recovery or withdrawal. 2) Document should be legible and include signature of a manager of Production or Quality Control department and the signed date. 3) An author, a reviewer (or a confirming person) or authorizer of a document should use his/her signature after registration of the signature. 4) All record documents should be prepared at the time of performing the activities and be written with indelible ink. Corrections to records should be made by stroking out the original records to leave the original record still readable and dated and signed by the person who corrected it. 5) When a document has been revised reason for revision and date of revision should be written and the revised document should be approved by a manager of Production or Quality Control department. Documents should be regularly reviewed and checked if it is kept up-to-date before revision. Superseded documents should also be retained for a certain period of time. 5.2. Document management 1) All record documents including electronic ones should be retained for a year after the expiry date of the product batch. For exceptional cases reason of exception and retention period should be clearly specified. 2) If documentation is handled by electronic data processing methods, only authorized persons should be able to enter, modify or delete data in the computer and records electronically stored should be

protected from being deleted or damaged by back-up transfer on magnetic tape, microfilm or other means. If necessary the records can be printed out as readable manner. 6. Validation 6.1. Subjects of conducting validation 1) Validation should be performed for the following occasions. However it is exempted for non-sterile products of herbal medicines or drugs used for clinical trials. Where manufacturing a drug product for the first time ① Where installing machinery or equipment which affect quality of the drug product ② Where there are changes in manufacturing processes ③ which affect quality of the drug product ④ Where there are changes in manufacturing environment 2) Standard documents on conducting validation and a comprehensive report which includes validation results and conclusion should be prepared and kept by a site. 3) If improvements on production control or quality control are required as a result of validation necessary actions should be taken and records about these actions should also be prepared and kept. 4) Validation can be omitted where there are objective and rational evidence data based on what a head of KFDA states. 6.2. Process validation 1) Process validation should be performed to validate and make documentation that manufacturing process of a drug product produces products which are consistently manufactured and meet preestablished specifications and product characteristics. 2) Prospective validation should be performed for major processes which affect product quality. In an unavoidable case it can be replaced with concurrent or retrospective validation. 3) Process validation should be performed by product. (For sterile processes of a sterile product process validation should be performed by process.) 4) Process validation can be classified by time of validation conduction. ① Prospective validation a. Prospective validation should be completed before the commercial distribution of the drug product. Acceptance criteria on fluctuation factors affecting product quality (such as properties of raw material, operational condition and etc.) should be met based on prior research results.

b. Prospective validation should be performed for 3 sequential commercial batches with an actual production scale and assessed and then overall evaluation shall be made. In this case all 3 batches should be confirmed to be suitable. ② Concurrent validation a. Concurrent validation can be performed while manufacturing and selling the drug product if only prospective validation cannot be performed due to an unavoidable reason. Acceptance criteria on fluctuation factors affecting product quality (such as properties of raw material, operational condition and etc.) should be met. b. Concurrent validation should be performed for 3 sequential commercial batches with an actual production scale and assessed and then overall evaluation shall be made. In this case all 3 batches should be confirmed to be suitable. ③ Retrospective validation a. Retrospective validation can be performed if there have been no changes in drug product composition, manufacturing process, manufacturing facilities or equipment. Retrospective validation should be analyzed by statistical methods based on accumulated manufacturing and quality control records such as manufacturing records and quality control records in the past, stability data and etc. b. Batches selected for retrospective validation should be 10-30 consecutive batches which had been manufactured and marketed in the past including any batches that failed to meet specifications during the review period. ④ Revalidation Revalidation should be performed periodically for already validated manufacturing process or faculties/equipment or when there have been changes in raw material, manufacturing methods, manufacturing process and faculties/equipment which have huge impacts on product quality. 6.3. Validation of analytical methods Validation of analytical methods is to the suitability of analytical methods for product quality control in advance and to make documents about it. Validation of analytical methods should be performed by products. 6.4. Cleaning validation Cleaning validation is to whether or not the residue (such as drug material, cleaning agents or etc which were used during the prior working process.) on machines/equipment or etc. and to make documents about it. Cleaning validation should be performed by products.

6.5. Validation of manufacturing ing facilities Validation of manufacturing ing facilities is to systems ing drug product manufacture such as water supply system, air ventilation system and etc and to make document about it. Validation of manufacturing ing facilities should be performed by machines/equipment. 6.6. Computerized system validation Computerized system validation is to with high level of guarantee that the computerized system accurately analyzes, controls, records and processes data according to pre-determined specifications and to make document about it. Computerized system validation should be performed by machines/equipment/systems. 7. Quality control 7.1. Test control 1) A certificate of analysis which includes the following particulars should be issued for each test request. A certificate of analysis can be issued or controlled integrated with a test request form and a test order. Product name, lot number or control number, date of manufacture ① Test number ② Dates of receipt, test and evaluation ④ Test items, specifications, test results and evaluation of the results ⑤ Result of the evaluation ⑥ Name of a person who performed the test and signature of a person who evaluate whether it ed the test or not and of a middle reviewer 2) Raw materials, intermediate products and finished products which are verified as meeting specifications should only be used or released. If there is any deviation or out-of-specification obtained the cause should be investigated and then dispose the material. Intermediate product, however, can be used before decision on meeting specifications is made considering validation, stability test, annual quality evaluation and etc. 3) If quality of a raw material has been consistently homogenous so that it guarantees sufficient reliance on quality, the raw material can be tested against necessary test items according to the established procedures and criteria of receipt the material. However, identification and visual examination must be performed and full analyses should be performed periodically.

4) There should be a middle reviewer who confirms whether test records (including raw data) are correct and conform to established specifications. However, this is exempted for drug products used in clinical trials. 5) Evaluation to authorizing release of a finished product should be based on production record and test results of intermediates and a finished product. 6) All the records (including electronic records) obtained from tests such as graphs, calculation formula and etc should be retained. 7) Sampling should be conducted without contamination or alternation of quality and the container should be packed as before the sampling and marked to indicate that a sample has been taken. 8) Test equipment, measuring devices and recording devices should be calibrated and documented regularly based on the established plan. 9) Stability samples of a drug substance or a finished product should be taken by batch number or control number. Stability sample of a drug substance should be stored for a year after expiry date of final batch of a finished product which the drug substance sample were used for production and stability sample of a finished product should be stored for a year after its expiry date. 10) Stability samples of a drug substance or a finished product should be stored in the same package of the marketed products. The amount of sample which is enough to be tested for specified test items at least twice should be stored in a specified condition. However, if the commercial product is packed in large quantity small amount of sample in a large package or small package of sample which is consisted with the same packing material of the large one can be stored. 11) Management status of standard reference material, samples and major reagents should be recorded. 12) Packing materials should be checked against established specifications where there have been changes in labels and the amended packing materials should be kept. 13) Primary packing material which is directly the drug product should be confirmed if it changes the drug product or if it is harmful to human body before being used. 14) Water used in the manufacturing process, sampled at the point of use, should be tested regularly according to established test methods. 15) If a drug substance of which stability is changed over the time is stored for a long time the drug substance should be re-tested before use. 16) Animals being used for tests should be controlled properly and quarantined. Adequate records showing the history of their use should be maintained.

17) Acceptance evaluation should be carried out to check errors by test performer or test equipment whenever testing samples which was actually manufactured or used. It is exempted for non-sterile drugs which is herbal drugs for drugs for clinical trials. 7.2. Stability test 1) Stability tests should be conducted based upon an established plan. Shelf-life, packaging methods and storage condition of a finished product should be established based on the stability test results. 2) Stability study protocol should include the following particulars. ① Classification of stability study and storing condition (according to the KFDA’s notification on stability tests) ② Test intervals and scheduled test date ③ Test methods and specifications ④ Quantity of samples ⑤ Packing material (Should be the same material with the commercial product) 3) The first three commercial production batches should be tested for long-term stability to confirm the expiry date. However, where the test results shows that there has been changes in quality of the product the expiry date should be adjusted appropriately. 7.3. Annual quality evaluation 1) The batch production records and CoA for each batch of the finished product should be checked and then based on these, it should be evaluated if the products comply with the specs are being manufactured and if the standard production process is appropriate. The evaluation should include the following; ① Critical In-process control and Test results of products ② The record of investigation on the Out-of-specification (OOS) batch. ③ The record of control management on the process or test method change. ④ The result of stability evaluation

The record of returned or recalled products and complaints.

⑤

The record of actions for the correction.

⑥

2) Out-of-specification (OOS) or deviation to the evaluation results should be investigated and

then the necessary actions should be taken.

3) Quality evaluation should be regularly carried out annually and recorded.

8. Production Control

8.1 In-process Control

1) The batch production records including the following should be prepared for each batch. The

batch production records and the manufacturing instructions can be combined.

Product name, pharmaceutical form and description of the product

①

Batch number, date of manufacture and expiry date

②

Batch size

③

Quantitative composition, Input amount and test number for batch. In case of the input

④

amount is different from the standard amount, the reason of that and calculation basis.

Operations and yield for each process. If the process is out of the spec of yield control, the

⑤

reason of that.

The result of in

⑥

-process

check

and

the

actions

taken

to

correct

any

deviation, if occurred.

Name of workmen who performed critical process,

⑦

a signature of confirming person,

operation date and time.

T

est number or control number and samples of the packaging material.

⑧

The distinctive number or code of Major machiner

⑨

y · equipment

Particular things (observational things etc)

⑩

2) Access to production premises should be restricted to authorized personnel.

3) Before any processing operation is started, steps should be taken to ensure that the facilities

and equipment are clean.

4) The work area, containers and mechanical equipment should be labeled or identified with an

indication of the product being processed and batch number.

5) Intermediate product should be tested appropriately in the necessary process to guarantee

the homogeneous of products and should be controlled to be suitable for the finished product

specs.

6) Intermediate product should be put into the process rapidly and should be stored under the

appropriate conditions ensuring the quality.

7) Checks on yields should be carried as necessary to ensure that there are no discrepancies

outside acceptable limits. Any significant deviation from the expected yield should be

investigated and then the appropriate actions should be established and taken.

8) Special precautions should be taken to prevent the microbial contamination and the work

area should be controlled according to the Clean-Grade during the production.

9) In case products need sterilizing process, special precaution should be taken to prevent

confusing the non-sterilized product with sterilized products.

10) Checks on the quality of water used in the manufacture should be carried out according to

the specified procedure every operation.

11) For the re-processing of the Intermediate product which is Out-of-specification (OOS), it

should be approved by The Manager of Quality Control Department and the record should be

kept.

12) For the product which should take Pyrogen test, the container and stopper of product

should be washed and sterilized to get rid of a pyrogen.

13) In the critical process, if the operation time is out of the one specified to assure the quality of the finished product, it should be demonstrated that the deviation has no effect on the quality of products and the relevant records should be kept. 8.2. Control of packaging process

1) In case that packaging operations on different products or different manufacturing unit are carried out simultaneously or consecutively, the suitable plan such as segregation of work area should be made to avoid mix-up or cross-contamination of products and mix-up of materials. 2) Before any packaging operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any packaging materials used in the previous operation, 3) Printed packaging materials should be used after steps should be taken to ensure the approval of the quality (assurance) department and the correct performance of the printed content. In case that the material is printed during packaging line, it should be confirmed that the printed content meets the content indicated in manufacturing record. 4) The name and batch number of the product should be displayed at the work area, packaging lines, printing machines and other equipment. 5) Upon completion of a packaging operation, if there is discrepancies found between the number of packaging materials issued and the number of packaging materials used, it should be investigated. Any unused packaging materials should be returned to stock or destroyed after recording the quantities of packaging materials issued, used and returned. But, batch number-coded packaging materials should be destroyed. 6) The correct performance of printing and packaging operation should be checked and recorded. 7) After completion of a packaging operation, finished products should be stored under conditions for prevention of mix-up until the quality (assurance) department confirm that the product meets the specifications. 8) For container or packaging material of products, tests for identification of airtightness or sealing should be performed, if necessary. 9) Name of a person who performed the packaging operation and signature of a person who confirmed that fact. 8.3. Repackaging and Returns 1) For the returned products, the details for return including the name and batch number of the products, quantity of the returned products, the reason for return, consignee, date of the return, the handling of return and the date for the handling of return should be recorded. 2) The returned products from the market, restorage and repackaging are permitted only if they meet all the following conditions; ① Whether it is confirmed that they are stored in the appropriate storage condition ② Whether it is confirmed that the primary container is not damaged

③ whether expiry date is enough remained ④ whether it is confirmed that the test results of the products meet quality specifications 3) Restorage and repackaging operation should be approved by responsible person in quality (assurance) department. If the repackaging operation is needed, repackaging operation should be conducted for each products and batch number according to repackaging instructions and records and they should be stored again after it confirmed that the test results of the products meet quality specifications. 4) For repacked products, it should be noted that the repackaging was conducted for these products at batch number etc., and the expiry date should not be changed. 5) For the returned products which are not allowed for restorage or repackaging, they should be stored separately and destroyed promptly according to the standards. 9. Production Hygiene Control 9.1. Personnel hygiene 1) Personnel should wear specified an uniform, shoes, a cap, a mask and etc suitable for the manufacturing activity or clean areas with which they are involved. 2) Periodic medical check-up should be conducted for newly hired and working employees. 3) Personnel who might affect the product quality such as who is suffering from an infectious disease should not participate in manufacturing activities that he or she can directly with drug products. 9.2. Hygiene control of production area 1) Production areas should be arranged in order to avoid contamination and mix-ups and should be cleaned to maintain cleanliness. 2) Cleaning of production area should be carried out according to cleaning protocols about cleaning methods, cleaning period, cleaning confirmation and etc. 3) Clean area should be maintained and controlled based on its cleanliness grade and regularly checked. 4) Smoking and brining food in should be restricted to manufacturing or storing areas. 5) Anti-rodents and anti-insects measures should be adopted and checked and confirmed periodically. 9.3. Cleaning of manufacturing equipment 1) Detergents or sanitizer used for cleaning manufacturing equipment should not produce any residues or abnormality on the surface of applied equipment.

2) Cleaned manufacturing equipment should be maintained and controlled not to be contaminated until the next use. 3) Records of manufacturing equipment cleaning showing the date of the cleaning operation, the person who performed the cleaning, cleaning reagents which were used for the cleaning operation in chronological order and records of manufacturing machine or equipment use showing information of product processed in the equipment/machine in chronological order should be prepared and kept. Cleaning record and use record can be integrated together and maintained. 10. Control of raw materials and products 10.1. Receipt control 1) Received raw materials should be held under quarantine until they have been released for use. If a proper measure to clearly differentiate accepted materials from the others is adopted raw materials before acceptance can be stored with accepted ones. 2) Received raw material should be visually checked of its appearance and labels and stored after dust on outer packages removed and assigned with a control number if its batch number was not on the label. 3) Test samples should be taken from each batch number or control code number upon receipt of raw material. The container or package of the sample should be labeled with product name, batch number, date of sampling, the person who performed the sampling operation and etc. 10.2. Storage control 1) Access to storage areas should be restricted to a person who is not working for storing activities. . 2) Drug substances, packing materials, finished products, rejected products and returned products should be stored at designated sections and separated from each other. Where a proper storage system preventing mix-ups of raw materials and finished products is maintained, it is not, 3) Each batch or controlled number of Raw material and finished product should be labeled if it is before or after tests and stored separately. However if it is controlled by automated system they doesn’t need to labeled. 4) Raw materials and finished products should be stored not directly ing with wall or floor. They should be arranged in order and stored so that the oldest stock is used first. 5) Rejected raw materials should be labeled that it was rejected and should be quarantined from other raw materials and disposed quickly. 6) Raw Materials, intermediate products and finished products should be stored under conditions that have no adverse affect on their quality.

7) Packaging materials should be stored separately according to product and kinds of the materials. If there has been changes in label claims a proper measure to prevent mix-ups with obsolete packing materials should be established. 10.3. Storage control of crude herbs 10.4. Distribution Control 1) API, medicinal products, intermediate, raw material and so on should be released and distributed in storage order but shall not be done if there is an appropriate reason. 2) Raw material should be transferred to manufacturing unit when tested and considered to be appropriate by the quality unit(s) 3) API or finished medicinal products should only be distributed after they have been authorized to be released by the QP in quality unit(s). Name, batch number, distribution date, third party’s and quantity should be documented and controlled. 11. Complaints and Recalls 1) SOP on complaint handling should be in place and the board for complaint handling should be organized and operated in order to manage the complaints efficiently. 2) Complaints received from customer should be recorded and quickly investigated with its cause. Measure to prevent the recurrence should be prepared and the appropriate follow-up action should be taken to complainant. 3) Complaints records should include: ① Name and batch number of product ② Name and phone number of complainant or person submitting the complaint. ③Date complaint is received ④ Description of complaint ⑤ Any follow -up action taken; Response provided to the originator of complaint; final decision on product batch 4) The appropriate follow-up action should be taken, the record should be maintained and measure to prevent the recurrence should be set up and operated when there is a defect in distributed product 5) Returned product should be separately stored and reprocess, reworked or destroyed as appropriate. 12. Change Control

1) The potential impact on reappearance of the quality or process for product should be evaluated when facility or equipment, raw material, manufacturing process, analytical methods and so on is changed. For the change of item 12.1, the manufactured product should be confirmed to meet the quality control specification, through enough data. If necessary, validation should be performed with the exception of product for clinical trial 2) When the change is in place, the necessary action, for example the revision of related document and education/training of operator, should be performed. 13. Self-inspection (Internal audits) 1) Self-inspection should be conducted periodically based on an established plan to check if manufacturing and quality control conform with to this Korean GMP guidance. Additional self-inspection should be conducted for special occasions such as that there are frequent occurrence of out-ofspecification obtained or product recalls. 2) A person who can conduct self-inspection should be a manager of quality (assurance) department or a person designated by a manager of quality (assurance) department and should have enough knowledge and experience on this guidance. Self-inspection can be conducted by a contract agency where necessary. 3) Purpose and range of self-inspection should be established prior to conduction the inspection. Audit findings and corrective actions should be documented as an audit report. Agreed corrective actions should be completed in a specified timeline. 14. Education and training 1) A person responsible for training should be designated. Protocols of education and training which include contents and evaluation of education and training should be established. Education can be conducted by an external training agency where necessary. 2) Education and training of personnel engaged in the manufacturing works should be conducted based upon an established annual plan. The education and training should cover production control, quality control and other necessities to ensure personnel to perform responsible tasks efficiently. 3) Re-education should be conducted based on evaluation of training results. 15. Site inspection 15.1 Appraisal 1) The Minister of Korea Food and Drug istration shall make an appraisal of the application. 2) The manufacturer who wants to have an appraisal on the performance of GMP according to the paragraph 1, should have 3 lots or more (per finished pharmaceutical product) before the application day.

15.2 Decision 1) When the Minister of Korea Food and Drug istration reviews the application according to article 15.1, he may request the related Associations to review the application. 2) The Minister of Korea Food and Drug istration can inspect the site to determine whether the manufacturer is the appropriate one 3) Manufacturers or Importers shall bear the expenses for the inspection made hereunder. 15.3 Inspection Authorities 1) The Minister of Korea Food and Drug istration shall engage the Inspection Authorities among the pharmaceutical inspectors for the field inspection according to the paragraph 2 in article 15.2. 2) Inspection Authorities (Qualification as follows) should have a GMP inspection training. ① Pharmacist ② Or the person who have a full knowledge and experience on GMP