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Annex 1 Documentation required for periodic GMP compliance inspection 1. Outline of products and the manufacturing site subject to inspection
Form 1-3 in accordance with the Office Memorandum Documents Required by PMDA for the Application of GMP Compliance Inspection should be submitted (Revised version of Form 1-3 issued on October 25, 2010).

2. Site plan
Site plan which clearly shows the location of the manufacturing site with its surrounding areas should be submitted. Layout of all the buildings and facilities also needs to be included in the site plan.

3. Facilities and equipment

3.1 Plans of facilities and equipment Location and names of major equipment in the plans of facilities and equipment should be included. Plans of the relevant laboratories (including animal keeping facilities) should also be provided. Plans, in which flow of personnel and materials, classification of environmentally controlled areas and conditions of air pressure differential are clearly shown, should be submitted. Information of air handling system in each environmentally controlled area should be provided. In the following cases, containment conditions including each personnel and material flow, separate air handling system and differential air pressure need to be described. (a) Products with high pharmacological activity or toxicity such as -lactam antibiotics, certain steroids or cytotoxic substances are manufactured in the site. (b) Substances with toxic herbicide or pesticide or substances with high pharmacological activity or toxicity such as -lactam antibiotics, certain steroids or cytotoxic substances are manufactured in the API intermediates manufacturing sites. 3.2 Computerized System The following documents need to be submitted when the site has GMP computer system. (a) List of major GMP computer systems and their functions For example, Name of the system: ERP, MES, LIMS, DCS, etc.

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Functions: Material and product control, laboratory control, manufacturing control, batch release control, etc. (b) Documents covering the basic principles of computerized system validation For example, Summary of site policy of computer system management, containing reference to the regulations and names of the relevant guidelines (Establishment of handling procedures needs to be proved.)

4. GMP organization chart and quality assurance system

GMP organization chart and documents regarding quality assurance system should be submitted. Names and job titles of all the key personnel for GMP should be provided. If corporate quality assurance organization is involved, the relationship between the quality unit and the corporate unit needs to be clearly shown.

5. GMP related documents

A list of GMP related SOPs should be submitted (titles of each document, document numbers, etc. need to be given).

6. Manufacturing process
6.1 Flow chart of manufacturing process Names of the materials (or the representative product, the same shall apply hereinafter), such as raw materials, intermediates, intermediate products, finished products, etc. should be provided. Flow chart including process parameters, solvents, in-process control items, specifications, etc. (matters concerning design space should be provided, if applicable) also needs to be submitted. If solvent, mother liquor, isolated intermediate, product, etc. are to be reused, regenerated or reprocessed under the manufacturing flow, please describe so. 6.2 Process water Following documents of process water should be submitted. (a)Types and specifications of all the process water relevant to the product (b)When the site has own manufacturing equipment of process water, their operational flow chart and a copy of the procedure which stipulates routine control items (control items and specifications) should be submitted. Summary of the above documents may be substituted.

7. Validation status
7.1 Validation documents required for periodic inspection

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Documents described in the Chapter 3 Section 4 Validation Standards of Enactment, Revision or Repeal of Ministerial Ordinances and Notices Related to the Standards for Manufacturing Control and Quality Control of Drugs and Medical Devices(GMP/QMS) for the Enforcement of the Law for Partial Revision of the Pharmaceutical Affairs Law and the Blood Collection and Donation Services Law (PFSB/CND Notification No.0330001 dated March 30, 2005) for the batches manufactured after the previous inspection should be submitted. Submission of the annual product review (including results of the following validations) should suffice. (a) Revalidation for changes A summary table of reports including titles, execution date and results of all the validations, which were performed as a part of change control works for the changes of raw materials, packaging materials, manufacturing process or facilities and equipment should be submitted. (b) Periodical revalidation Documents which summarize frequency and results of periodical revalidation as required for sterilization process, etc. executed within past two years should be submitted. (c) Periodical review of in-process control Summary of review results from the routine in-process control, test results, etc. should be submitted. If metal catalyst or solvents classified into Class I or II of ICHQ3(R3) are used in the process and residues of which are not subject to the specifications or to the periodical review of in-process control, the result of residue evaluation needs to be provided. 7.2 Documentation of cleaning validation A copy of the cleaning validation standards (cleaning validation procedure) or their summary documents should be submitted. In cases of (a) or (b) below, a copy of the validation report or its overview documents need to be provided in order to prove absence of cross contamination to the product(s) subject to inspection. The document should contain information of applicable equipment, cleaning methods, evaluation items and limit values. (a)Products with high pharmacological activity or toxicity such as -lactam antibiotics, certain steroids or cytotoxic substances are manufactured in the multi-purpose equipment/facilities. (b)Materials with toxic herbicide, pesticide or substances with high pharmacological activity or toxicity such as -lactam antibiotics, certain steroids or cytotoxic substances are produced in the multi-purpose equipment/facilities in API intermediates manufacturing sites.

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8. Manufacturing history
A list of lots manufactured in each year up to the previous inspection and annual production volume, etc. of all the products subject to inspection should be provided.

9. Release control
Following documents concerning the release control in the manufacturing site should be submitted. (a)A copy of the batch release procedure (the procedure of batch record review, QC record review and other checks at the time of batch release) or its overview documents (b)A copy of the batch release procedure or its overview documents when real time release or parametric release is applied.

10 Deviation control
10.1 Documents of deviation control procedure Deviation control procedure or its overview documents should be submitted. 10.2 Documents of actual record of deviation control A list, etc. of actual deviation control records executed after the previous inspection should be submitted. If none of the deviation has occurred, please describe so.

11. Change control

11.1 Documents of change control A copy of the change control procedure and its overview documents should be submitted. 11.2 Documents of actual change control record An overview list of actual change control record executed after the previous inspection should be submitted. If no change has been made, please describe so.

12. Compliance to the Standards for Biological Ingredients

Documents to prove compliance to the Standards for Biological Ingredients for all the products subject to inspection should be submitted. If no raw material subject to stipulations of the Standards for Biological Ingredients is used, please describe so.

Notes
1. The above described documents are standard requirements. However, necessary documents may vary depending on the products or the manufacturing process subject to inspection. Submission of copy of the manufacturing instructions, master batch records, master test records and

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the test inspection procedure may be requested depending on the results from the previous GMP inspection. Please follow instructions from inspectors. 2. When most of the documents are written in foreign languages except English, please submit overview documents written in Japanese or English. 3. If manufacturer(s) of the product subject to inspection needs to submit the documentations directly to PMDA, please consult with responsible inspectors and follow their instructions. 4. When the above documents have already been submitted to PMDA for the previous inspection within the past 2 years (including desk-top inspections), submission of documentations as to the changed items or the parts after the previous inspection should suffice. For the items to which no change has been made, please provide information of the previous inspection (name of the marketing authorization holder, system registration number, products subject to inspection and application date) and specify the submitted documents in the previous inspection. 5. When GMP certificate (limited to original copy) from MRA member country is attached, submission of documents from No.2 till No.11 can be omitted. When GMP certificate (limited to only original copy) from MOU member country is attached, submission of the above documents can be omitted in some cases. For further information, please consult with responsible inspectors. 6. When the site master file contains the same information as requested by PMDA, it can be replaced with master file submission (in English or Japanese). 7. If there is any document without approval of responsible person of the site (qualified person in the EU, head of quality unit in other countries), such as summary prepared specially for the purpose of GMP application, excerpt of CTD contents, documents without GMP control number, etc., please attach a statement signed by the responsible person of the site, certifying that the content of such document is a true reflection of the documentation of the site.