Thông tư 35/2018/TT-BYT về Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc

THE MINISTRY OF HEALTH

CircularNo. 35/2018/TT-BYT datedNovember 22, 2018 of the Ministry of Health good manufacturing practices for pharmaceutical products and pharmaceutical starting materials

Pursuant to the Law on Pharmacy No. 105/2016/QH13 dated April 06, 2016;

Pursuant to the Government’s Decree No. 54/2017/ND-CP dated May 08, 2017 on guidelines for implementation of the Law on Pharmacy;

Pursuant to the Government’s Decree No. 155/2018/ND-CP dated November 12, 2018 on amendments to some Articles related to business conditions under state management of the Ministry of Health;

Pursuant to the Government’s Decree No. 75/2017/ND-CP dated June 20, 2017 defining functions, tasks, entitlements and organizational structure of the Ministry of Health;

At the request of the General Director of the Drug Administration of Vietnam and the General Director of the Traditional Medicine Administration of Vietnam,

The Minister of Health hereby promulgates a Circular on Good Manufacturing Practices for pharmaceutical products and pharmaceutical starting materials.

Chapter I

GENERAL PROVISIONS

Article 1. Scopeof regulation

This Circular provides for application and promulgation of Good Manufacturing Practices for pharmaceutical products and pharmaceutical starting materials (hereinafter referred to as “GMP”) and inspection of GMP compliance.

Article 2. Definitions

For the purposes of this Circular, the terms below shall be construed as follows:

1. “Good Manufacturing Practices”(GMP) means a set of principles and standards for manufacture of pharmaceutical products and pharmaceutical starting materials to ensure that pharmaceutical products and pharmaceutical starting materials are consistently manufactured and controlled to the quality standards appropriate to their intended use and as required by the certificate of pharmaceutical product and pharmaceutical starting material registration.

2. “Manufacturer”(including manufacturers of chemical pharmaceutical products, herbal pharmaceutical products, vaccines, biologicals, traditional pharmaceutical products, traditional ingredients, traditional ingredients, pharmaceutical starting materials) means a pharmacy establishment that is required or not required to obtain Certificates of eligibility for pharmacy business and enters one, some or all stages of the process of manufacturing pharmaceutical products and pharmaceutical starting materials.

3. “Deficiency”means a deviation from GMP principles or other applicable regulations on pharmacy management.

4. “GMP”stands for Good Manufacturing Practices.

5. “WHO”stands for World Health Organization.

6. “WHO - GMP”means Good Manufacturing Practices of World Health Organization.

7. “PIC/S”stands for Pharmaceutical Inspection Co-operation Scheme.

8. “PIC/S - GMP”means Good Manufacturing Practices of Pharmaceutical Inspection Co-operation Scheme.

9. “EU”stands for European Union.

10. “EU - GMP”meansGood Manufacturing Practices of European Union.

11. “US”stands for United States.

12. “SRA”stands for Stringent Regulatory Agency.

Chapter II

APPLICATION AND PROMULGATION OF GMP

Article 3. Documents about GMP principles

1. The following GMP principles shall be applied:

a) WHO GMP principles provided in the Appendix I hereof and updated documents specified in Clause 3 of this Article;

b) Principles of WHO - GMP for biological medicinal products derived from Human Blood or Plasma provided in the Appendix II hereof and updated documents specified in Clause 3 of this Article;

c) GMP principles of Pharmaceutical Inspection Co-operation Scheme provided in the Appendix I hereof and updated documents specified in Clause 3 of this Article;

d) EU - GMP principles provided in the Appendix IV hereof and updated documents specified in Clause 3 of this Article.

2. The following GMP principles shall be promulgated:

a) Principles of GMP for herbal pharmaceutical products provided in the Appendix V hereof;

b) Principles of GMP for traditional pharmaceutical products provided in the Appendix VI hereof;

c) Principles of GMP for traditional ingredients provided in the Appendix VII hereof.

3. In addition to the GMP principles specified Clauses 1 and 2 of this Article, other GMP principles proved equivalent to EU - GMP principles promulgated by pharmacy authorities of SRA countries shall be applied. Manufacturers of pharmaceutical products and pharmaceutical starting materials that apply GMP shall translate and certify translations as prescribed by the law on notarization and authentication and submit them to the Drug Administration of Vietnam to be posted on the web portal of the Ministry of Health and website of the Drug Administration of Vietnam.

4. In the cases where WHO, PICS, EU or pharmacy authorities of SRA countries make any revision to GMP principles (hereinafter referred to as “updated documents) specified in Clause 1 of this Article, within 06 months from the date on which updated documents are published on websites of such authorities, the Drug Administration of Vietnam shall translate them and publish the revisions on the web portal of the Ministry of Health and websites of the Drug Administration of Vietnam and Traditional Medicine Administration of Vietnam.

Article 4. Application of GMP principles

1. Manufacturers of pharmaceutical products and pharmaceutical starting materials shall apply GMP principles specified in the Appendix I or Appendix III or Appendix IV hereof and updated documents specified in Clause 4 Article 3 hereof.

2. Manufacturers of biological medicinal products derived from human blood or plasma shall apply GMP principles specified in the Appendix II hereof and updated documents specified in Clause 4 Article 3 hereof.

3. Manufacturers of herbal pharmaceutical products shall apply GMP in accordance with regulations specified in Appendix V hereof.

4. Manufacturers of traditional pharmaceutical products in ointment, pill, pellet or powder forms shall apply GMP principles specified in Part I - Appendix VI hereof.

5. Manufacturers of traditional pharmaceutical products in modern dosage forms (capsules, tablets, granules, liquid medicines and other modern dosage forms) other than those specified in Clause 4 of this Article shall apply GMP principles specified in Part II - Appendix VI hereof.

6. Manufacturers of traditional ingredients shall apply GMP principles specified in Appendix VII hereof.

7. Manufacturers of pharmaceutical products and pharmaceutical starting materials are entitled to apply other GMP principles proved equivalent to EU - GMP principles promulgated by pharmacy authorities of SRA countries and updated documents specified in Clause 4 Article 3 hereof.

8. Manufacturers of herbal pharmaceutical products, traditional pharmaceutical products and traditional ingredients shall apply GMP principles specified in the Appendix I or Appendix III or Appendix IV hereof and updated documents specified in Clause 4 Article 3 hereof.

9. Manufacturers of traditional pharmaceutical products and traditional ingredients are entitled to apply GMP principles specified in Part II Appendix VI or Appendix I or Appendix III or Appendix IV hereof and updated documents specified in Clause 4 Article 3 hereof.

10. In addition to being manufactured by the manufacturer applying corresponding GMP specified in this Article, pharmaceutical products and pharmaceutical starting materials containing beta-lactam antibiotics (Penicillins, Cephalosporins, Penems and equivalent), cytotoxics/cytostatics, sexual hormone, substances with hormonal activity, vaccines, biologicals and pharmaceutical products with special requirements specified in GMP must be manufacturered at separate premises, which has particular equipment and a plan for prevention of release of such pharmaceutical products, which is likely to affect the environment and other pharmaceutical products manufactured in the same area.

11. Manufacturers of chemical pharmaceutical products in the form of soft capsules, oral liquids and external medicines (creams, gels, ointments and lotions) are entitled to manufacture herbal pharmaceutical products from herbal extract, glue and granule that have been standardized on the production line and have corresponding dosage form, and must apply GMP principles specified in the Appendix I or Appendix III or Appendix IV hereof and updated documents specified in Clause 4 Article 3 hereof.

12. Manufacturers of herbal pharmaceutical products are entitled to manufacture herbal pharmaceutical products with added pure ingredients extracted from essential oils, vitamins and minerals, and must apply GMP principles specified in the Appendix V hereof.

13. Manufacturers of traditional pharmaceutical products are entitled to manufacture traditional pharmaceutical products with added pure ingredients extracted from essential oils, vitamins and minerals, and must apply GMP principles specified in the Appendix VI hereof.

14. Manufacturers entering one or some stages of the process of manufacturing pharmaceutical products and pharmaceutical starting materials shall apply and comply with corresponding GMP principles mentioned in Clauses 1, 2, 3, 4 and 5 of this Article.

15. Manufacturers of pharmaceutical products and pharmaceutical starting materials shall apply updated documents specified in Clause 3 Article 3 hereof within:

a) 12 months in case of any change of premises or manufacturing equipment, from the date on which updated documents are published on the website of the Ministry of Health and web portal of the Drug Administration of Vietnam;

b) 06 months in case of updates other than those specified in Point a of this Clause, from the date on which updated documents are published on the website of the Ministry of Health and web portal of the Drug Administration of Vietnam.

Chapter III

INSPECTION OF GMP COMPLIANCE

Article 5. Documents used as basis for inspection of GMP compliance

1. Documents used as basis for inspection of GMP compliance by a pharmacy business establishment are those included in its application for certificate of eligibility for pharmacy business (the establishment is not required to submit these documents because they have been submitted when it applies for the certificate of eligibility for pharmacy business) prescribed in Article 38 of the Law on Pharmacy and Article 32 of the Government’s Decree No. 54/2017/ND-CP dated May 08, 2017 on guidelines for the implementation of the Law on Pharmacy (hereinafter referred to as “the Decree No. 54/2017/ND-CP”).  Manufacturers of special-controlled pharmaceutical products must have the documents prescribed in Article 38 of the Law on Pharmacy and Clause 31 Article 5 of the Government’s Decree No. 155/2018/ND-CP dated November 12, 2018 on amendments to some Articles related to business conditions under state management of the Ministry of Health (hereinafter referred to as “the Decree No.155/2018/ND-CP”).

Technical documents about a manufacturer shall be prepared in accordance with guidelines for the site master file provided in the Appendix VIII hereof or the site master file that is updated in the case of change of scope of operation.

2. If a manufacturer applies for both certificate of GMP compliance and certificate of eligibility for pharmacy business, this content and applied GMP principles must be clearly specified in its application form for certificate of eligibility for pharmacy business.

3. If the manufacturer applying for certificate of eligibility for pharmacy business sells pharmaceutical products and pharmaceutical starting materials to wholesalers, retailers or health facilities, documents about its technologies and personnel according to Clause 2 Article 32 of the Decree No. 54/2017/ND-CP are required when it applies for both certificate of GDP compliance and certificate of eligibility for pharmacy business. The receiving authority shall inspect its compliance with both GDP and GMP in accordance with regulations on GDP.

Article 6. Sequence of inspection of GMP compliance

1. Receipt of applications:

The manufacturer shall submit an application, which includes the documents specified in Article 5 herein, accompanied by the application fees in accordance with regulations of the Minister of Finance to:

a) The Traditional Medicine Administration of Vietnam if the manufacturer applies for the certificate for eligibility for pharmacy business that allows manufacture of herbal ingredients, traditional pharmaceutical products and traditional ingredients at the time of submission;

b) The Drug Administration of Vietnam if the manufacturer applies for the certificate for eligibility for pharmacy business that allows manufacture of pharmaceutical starting materials (excluding herbal ingredients), chemical pharmaceutical products, herbal pharmaceutical products, vaccines and biologicals;

c) The Drug Administration of Vietnam if the manufacturer applies for the certificate for eligibility for pharmacy business that allows manufacture of both one of the pharmaceutical products and pharmaceutical starting materials specified in Point a of this Clause and one of the pharmaceutical products and pharmaceutical starting materials specified in Point b of this Clause at the time of submission.

2. Sequence of receiving and processing applications is prescribed in Clauses 2 and 5 Article 33 of the Decree No. 54/2017/ND-CP and Clause 12 Article 5 of the Decree No. 155/2018/ND-CP.

3. Within 05 days from the receipt of the satisfactory application, the receiving authority shall establish an inspectorate and send the manufacturer the decision on inspectorate establishment specifying expected date of the site inspection.

Within 15 days from the date of issuing the decision, the inspectorate shall carry out a site inspection of the manufacturer.

Article 7. Procedures for inspection and classification of GMP compliance

1. Principles of using GMP documents for inspection of GMP compliance:

a) GMP documents are applied by the manufacturer and specified in the application form for certificate of eligibility for pharmacy business.

b) EU - GMP or PIC/S - GMP or GMP documents specified in Clause 3 Article 3 of this Article are applied if the manufacturer has undergone GMP inspection by SRA and been recommended by SRA to make the declaration of compliance with GMP.

c) WHO - GMP or GMP documents specified in Clauses 2, 3, 4, 5 and 6 Article 4 of this Circular are applied if the manufacturer does not specify applied GMP principles in the application form for certificate of eligibility for pharmacy business.

2. Inspection procedures:

a) Step 1. The inspectorate shall publish the decision on inspectorate establishment, purposes, contents and plan for the inspection at the manufacturer;

b) Step 2. The manufacturer shall make a brief introduction of its organizational structure, personnel and implementation or application of GMP, or specific contents in conformity with the inspected contents;

c) Step 3. The inspectorate shall carry out a site inspection of the application of GMP at the manufacturer. If the manufacturer enters one or some stages of the manufacturing process, only GMP applied to such stages is inspected;

d) Step 4. The inspectorate shall have a talk with the manufacturer about deficiencies found during the inspection (if any) and assess the level of each deficiency; discuss with the manufacturer in case the manufacturer does not agree with the inspectorate about the assessment of each deficiency or level of GMP compliance;

dd) Step 5. An inspection record is prepared and signed as follows:

After the site inspection, the inspectorate shall make an inspection record using the Form No. 03 in the Appendix X hereof. It shall clearly specify members of the inspectorate and the manufacturer, location, date and scope of the inspection and disagreements (if any) between the inspectorate and the manufacturer. It shall be signed by the head of the manufacturer and chief of the inspectorate. The record shall be made into 03 copies, among which one is kept by the manufacturer and the others are kept by the receiving authority.

e) Step 6. The inspection record is completed as follows:

The inspectorate shall make a GMP inspection report using the Form No. 04 in the Appendix X hereof, list, analyze and classify deficiencies that need to be rectified by the manufacturer, make a comparison of corresponding regulations specified in legal documents and GMP, and assess the level of GMP compliance. The deficiency classification and assessment of level of GMP compliance (applied to each production line) are prescribed in the Appendix IX hereof.

3. Level of GMP compliance:

The inspection of manufacturer s compliance with GMP specified in Appendix IX hereof shall be carried out according to the following 04 levels:

a) GMP level 1 manufacturer;

b) GMP level 2 manufacturer;

c) GMP level 3 manufacturer;

d) GMP level 4 manufacturer.

Article 8. Processing results of inspection of GMP compliance

1. If the GMP inspection report indicates that the manufacturer complies with GMP at level 1 as prescribed in Point a Clause 3 Article 7 of this Circular:

Within 10 working days from the date of signing the inspection record, the receiving authority shall request the Minister of Health to issue the certificate of eligibility for pharmacy business and issue the Certificate of GMP compliance according to Form No. 05 in the Appendix X hereof if the manufacturer applies for both certificate of GMP compliance and certificate of eligibility for pharmacy business.

2. If the GMP inspection report indicates that the manufacturer complies with GMP at level 2 as prescribed in Point b Clause 3 Article 7 of this Circular:

a) Within 05 working days from the date of signing the inspection record, the receiving authority shall send the GMP inspection report to the manufacturer as prescribed in Point b Clause 6 Article 33 of the Decree No. 54/2017/ND-CP.

b) Upon completion of deficiency rectification, the manufacturer shall submit a rectification report including a plan and evidences (such as documents, images, videos, certificates or other documentary evidences) for completion of rectification of deficiencies specified in the GMP inspection report;

c) Within 20 days from the receipt of the rectification report, the receiving authority shall assess result of deficiency rectification by the manufacturer and conclude the level of its GMP compliance. To be specific:

- If the result of deficiency rectification makes the manufacturer comply with GMP, the receiving authority shall request the Minister of Health to issue the certificate of eligibility for pharmacy business and the certificate of GMP compliance according to the Form No. 05 in the Appendix X hereof if the manufacturer applies for both certificate of GMP compliance and certificate of eligibility for pharmacy business;

- If the result of deficiency rectification shows that the manufacturer still fails to comply with GMP, the receiving authority shall respond and provide explanation in writing.

d) Within 06 months from the date on which additional documents are requested in writing by the receiving authority, the manufacturer shall submit them as requested. If the manufacturer fails to satisfy such request by the aforementioned deadline or the application is not satisfactory within 12 months from the first time it is submitted, the application will be rejected.

3. If the GMP inspection report indicates that the manufacturer complies with GMP at level 3 as prescribed in Point c Clause 3 Article 7 of this Circular:

Sequence and time of processing result of inspection of GMP compliance are specified in Clause 2 of this Article.

Within 20 days from the receipt of the rectification report, the receiving authority shall carry out a site inspection of deficiency rectification at the manufacturer before concluding the level of GMP compliance as prescribed in Point c Clause 2 of this Article.

4. If the GMP inspection report indicates that the manufacturer complies with GMP at level 4 as prescribed in Point d Clause 3 Article 7 of this Circular:

Within 05 working days from the date of signing the inspection record, the receiving authority shall send a notification of failure to comply with GMP enclosed with a GMP inspection report to the manufacturer and shall not issue the certificate of eligibility for pharmacy business.

5. In the cases where the manufacturer does not agree with the deficiency stated by the inspectorate, within 30 days from the date on which the inspectorate sends GMP inspection report or rectification report, the manufacturer shall submit a written recommendation enclosed with evidences (such as documents, images, videos and certificates) related to such deficiency to the receiving authority.

Within 10 working days from the receipt of the written recommendation, the receiving authority shall review GMP inspection report and written recommendation submitted by the manufacturer, if necessary, consult relevant exports and respond to the manufacturer in writing. The written response must clearly specify agreements and disagreements with the written recommendation submitted by the manufacturer and reasons for disagreements. The abovementioned length of time shall not add to the time limit for inspection.

6. Within 05 working days from the date of issuing the certificate of eligibility for pharmacy business, the receiving authority shall publish the following information on its website and web portal of the Ministry of Health:

a) Name and address of the manufacturer;

b) Full name of the person in charge of pharmacy, person in charge of quality assurance and number of his/her pharmacy practicing certificate;

c) Number of the certificate of eligibility for pharmacy business and Certificate of GMP compliance (if any);

d) Expiry date of inspection of GMP compliance;

dd) Scope of operation of the manufacturer;

e) EU - GMP certificate number, effective period and issuing authority if the manufacturer has its compliance with EU - GMP or equivalent inspected by SRA.

Chapter IV

INSPECTION OF GMP COMPLIANCE AND MAINTENANCE THEREOF

Article 9. Periodic inspection of GMP compliance

1. GMP compliance by a manufacturer shall be periodically inspected every 03 year from the date of signing the previous inspection record (except unexpected inspections or audits by the Ministry of Health or the Provincial Department of Health).

2. In November, every receiving authority shall publish the plan for periodic inspection of GMP compliance by manufacturers in the succeeding year on its website and send it to manufacturers that are mentioned in the plan. Regarding the manufacturer specified in Point c Clause 1 Article 6 of this Circular, the Drug Administration of Vietnam shall publish and implement the periodic inspection plan, except in the cases where the manufacturer applies for a particular inspection.

3. At least 30 days prior to the date of carrying out periodic inspection of GMP compliance according to the published plan, the manufacturer shall submit a report on its manufacture of pharmaceutical products and pharmaceutical starting materials and GMP compliance (hereinafter referred to as “operation and GMP compliance report”) according to the Form No. 2 in the Appendix X hereof enclosed with updated technical documents about infrastructure, technologies and personnel of the manufacturer (in case any change is made) to the receiving authority.

E.g.: If the estimated date of periodic inspection of the manufacturer A is on August 18, 2018, the manufacturer A is required to submit an operation and GMP compliance report to the receiving authority by July 18, 2018.

4. If the manufacturer fails to submit the operation and GMP compliance report within the time limit prescribed in Clause 3 of this Article, within 15 days from the deadline for submission of the report, the receiving authority shall request the manufacturer in writing to submit the operation and GMP compliance report as prescribed.

5. Within 45 days from the date on which the operation and GMP compliance report is requested in writing by the receiving authority, the manufacturer shall submit the report enclosed with a written explanation for its delay in submission. By the aforementioned deadline, if the manufacturer fails to submit the report, the receiving authority shall carry out an unexpected inspection or audit of GMP compliance by the manufacturer as prescribed in Article 12 of this Circular.

6. After submitting the operation and GMP compliance report within the prescribed time limit, the manufacturer is entitled to keep manufacturing pharmaceutical products and pharmaceutical starting materials within the scope specified in the certificate for eligibility for pharmacy business until the result of periodic inspection of GMP compliance is available and shall ensure its maintenance of GMP compliance.

7. Sequence of inspecting and procedures for inspecting and classifying results of inspection of GMP compliance are prescribed in Articles 6 and 7 of this Circular.

Article 10. Processing of results of periodic inspection of GMP compliance

1. If the GMP inspection report indicates that the manufacturer complies with GMP at level 1 as prescribed in Point a Clause 3 Article 7 of this Circular:

Within 10 working days from the date of signing the inspection record, the receiving authority shall update information about the maintenance of GMP compliance by the manufacturer on its website and web portal of the Ministry of Health as prescribed in Clause 6 Article 8 of this Circular and issue the Certificate of GMP compliance according to Form No. 05 in the Appendix X hereof if the manufacturer applies for the certificate of GMP compliance.

2. If the GMP inspection report indicates that the manufacturer complies with GMP at level 2 as prescribed in Point b Clause 3 Article 7 of this Circular:

a) Within 05 working days from the date of signing the inspection record, the receiving authority shall send the GMP inspection report to the manufacturer so that it can rectify deficiencies and send a rectification report to the receiving authority;

b) Within 45 days from the date on which the receiving authority sends the GMP inspection report, the manufacturer shall submit a rectification report including a plan and evidences (such as documents, images, videos, certificates or other documentary evidences) for completion of rectification of deficiencies specified in the GMP inspection report;

c) Within 20 days from the receipt of the rectification report, the receiving authority shall assess result of deficiency rectification by the manufacturer and conclude the level of its GMP compliance. To be specific:

- If the result of deficiency rectification makes the manufacturer comply with GMP, the receiving authority shall update information about the maintenance of GMP compliance by the manufacturer on its website and web portal of the Ministry of Health as prescribed in Clause 6 Article 8 of this Circular and issue the Certificate of GMP compliance according to Form No. 05 in the Appendix X hereof if the manufacturer applies for the certificate of GMP compliance;

- If the result of deficiency rectification shows that the manufacturer still fails to comply with GMP, the receiving authority shall request the manufacturer in writing to take more corrective actions against deficiencies and submit an additional report. The manufacturer shall have 45 days from the receipt of the written request to complete corrective actions and send report thereof as requested.

d) Within 90 days from the date of signing the inspection record, if the manufacturer fails to submit the rectification report or still fails to comply with GMP after rectifying deficiencies, the receiving authority shall send a notification of failure to comply with GMP and impose one or some measures prescribed in Points and b Clause 4 of this Clause depending on the nature and level of non-compliance with GMP.

3. If the GMP inspection report indicates that the manufacturer complies with GMP at level 3 as prescribed in Point c Clause 3 Article 7 of this Circular:

Sequence and time of processing result of inspection of GMP compliance are specified in Clause 2 of this Article.

Within 20 days from the receipt of the rectification report, the receiving authority shall carry out a site inspection and supervision of deficiency rectification at the manufacturer before concluding the level of GMP compliance as prescribed in Point c Clause 2 of this Article.

4. If the GMP inspection report indicates that the manufacturer complies with GMP at level 4 as prescribed in Point d Clause 3 Article 7 of this Circular:

Within 05 working days from the date of signing the inspection record, according to the assessment of risks of deficiencies in the quality of pharmaceutical products and pharmaceutical starting materials, and pharmaceutical product user safety, the receiving authority shall send a notification of failure to comply with GMP enclosed with a GMP inspection report. Depending on the nature and level of non-compliance with GMP, the receiving authority shall impose one or some of the following measures:

a) Impose penalties for administrative violations in accordance with regulations of the Law on penalties for administrative violations;

b) Request the Minister of Health to issue a decision on revocation of the certificate of eligibility for pharmacy business as prescribed in Clause 2 Article 40 of the Law on Pharmacy and revoke the certificate of GMP compliance (if any).

c) If the manufacturer is ineligible for one or several business activities specified in its certificate of eligibility for pharmacy business, the receiving authority shall:

- Request the Minister of Health to issue a decision on revocation of the certificate of eligibility for pharmacy business to remove the business activity for which the manufacturer is ineligible and issue a new certificate of eligibility for pharmacy business which is conformable with the business activity for which the manufacturer is eligible;

- Issue the certificate of GMP compliance which is conformable with the business activity for which the manufacturer is eligible if it so wishes.

5. Within 05 working days from the date of concluding that the manufacturer maintains its compliance with GMP or issuing the decision on revocation of the issued certificate of eligibility for pharmacy business because of the manufacturer’s failure to maintain GMP compliance, the receiving authority shall update GMP compliance status on its website as prescribed in Clause 6 Article 8 of this Circular if the manufacturer complies with GMP or information about the revocation of the certificate of eligibility for pharmacy business or Certificate of GMP compliance (if any) if the manufacturer fails to maintain its GMP compliance.

6. If it is concluded that a sample of pharmaceutical product or pharmaceutical starting material collected by the inspectorate during the inspection violates quality regulations, the receiving authority shall handle it in accordance with applicable regulations.

Article 11. Control of changes

1. Before making one of the changes specified in Points a and b of this Clause, a vaccine manufacturer shall send a notification including the result of assessment of risks and effect of changes expected to be made on the product quality and safety:

a) Changes specified in Points d, dd, e and g Clause 2 of this Article;

b) Manufacture or trial manufacture of vaccines or other pharmaceutical products on the vaccine production line that has been certified;

Within 15 days, the Drug Administration of Vietnam shall respond in writing in case it does not agree with the changes proposed by the vaccine manufacturer.

2. After making any changes, the manufacturer shall apply for the certificate of eligibility for pharmacy business or submit a report on its changes using the Form No. 06 in the Appendix X hereof if:

a) Making one of the changes specified in Point b Clause 1 Article 36 of the Law on Pharmacy; or

b) Changing the location of a factory at the same business location; or

c) Opening a new factory at the same business location; or

d) Expanding existing factory; or

dd) Repairing or having significant changes in structure and floor plan of the premises and production line, which results in changes to environmental conditions and manufacturing process; or

e) Changing important manufacturing equipment, thereby affecting manufacturing process and quality of pharmaceutical products and pharmaceutical starting materials; or

g) Changing auxiliary system or principle of designing and operating utility systems, thereby affecting manufacturing environment; or

b) Changing applied GMP and undergoing inspection of compliance with EU - GMP or equivalent (Japan - GMP, US - Current GMP, PIC/S -GMP) by SRA and being recommended by SRA to make the declaration of compliance with GMP.

3. In case of changes specified in Point a Clause 2 of this Article, the manufacturer shall submit an application for the certificate of eligibility for pharmacy business as prescribed in Clause 2 and Clause 4 Article 38 of the Law on Pharmacy.

Sequence of inspecting, classifying and processing the result of inspection of GMP compliance is specified in Articles 6, 7 and 8 of this Circular.

4. If the manufacturer has one of the changes prescribed in Points b, c, d or h Clause 2 of this Article or the manufacturer of sterile pharmaceutical products and pharmaceutical starting materials has the change specified in Point dd Clause 2 of this Article, the manufacturer is required to submit a report on its changes, accompanied by relevant technical documents, to the receiving authority.

a) The receiving authority shall carry out a site inspection at the manufacturer. If the manufacturer complies with GMP, the receiving authority shall grant a written consent to its changes;

b) Sequence of inspecting, classifying and processing the result of inspection of GMP compliance in case of the change specified in Point b Clause 2 of this Article is prescribed in Articles 6, 7 and 10 of this Circular;

c) Sequence of inspecting, classifying and processing the result of inspection of GMP compliance by the manufacturer that makes the change specified in Point c or d Clause 2 of this Article or the manufacturer of sterile pharmaceutical products and pharmaceutical starting materials that makes the change specified in Point dd Clause 2 of this Article is prescribed in Articles 6, 7 and 8 of this Circular.

5. In case of the change specified in Point h Clause 2 of this Article, the manufacturer shall send a notification of change of applied GMP and inspection by SRA at the manufacturer (name of SRA, date of inspection, content/scope of inspection and inspection result) enclosed with relevant technical documents, certificate of GMP compliance or GMP inspection report issued by SRA.

a) The receiving authority shall review the notification and enclosed documents and add/update information about compliance with EU - GMP or equivalent by the manufacturer as prescribed in Clause 6 Article 8 of this Circular.

b) The receiving authority shall inspect compliance with EU - GMP or equivalent by the manufacturer as prescribed in Article 12 of this Circular.

6. In case of one of the changes prescribed in Points dd, e or g Clause 2 of this Article (except in the cases specified in Clauses 4 and 6 of this Article), the manufacturer shall submit a report on its changes, accompanied by relevant technical documents, to the receiving authority. The receiving authority shall assess the manufacturer’s report on changes.

a) Within 10 working days from the receipt of the report on changes, the receiving authority shall notify the manufacturer in writing of approval for its changes if they meet requirements or issue a notification of deficiencies that need rectifying if its changes fail to meet with requirements;

b) Within 45 days from the receipt of the notification, the manufacturer shall complete deficiency rectification and send a rectification report enclosed with documentary evidences (such as documents, images, videos, certificates and other documentary evidences) for completion of rectification of deficiencies specified in the notification;

c) Within 10 days from the receipt of the rectification report enclosed with documentary evidences (such as documents, images, videos, certificates and other documentary evidences), the receiving authority shall assess result of deficiency rectification by the manufacturer and conclude the level of its GMP compliance. To be specific:

- If the result of deficiency rectification makes the manufacturer comply with GMP, the receiving authority shall notify the manufacturer in writing of approval for its changes;

- If the result of deficiency rectification shows the manufacturer still fails to comply with GMP, the receiving authority shall carry out an unexpected inspection and process inspection result as prescribed in Article 12 of this Circular.

7. If the manufacturer of non-sterile pharmaceutical products and pharmaceutical starting materials for external use has one of the changes prescribed in Points dd, e and g Clause 2 of this Article, the manufacturer is required to submit a report on its changes, accompanied by relevant technical documents, to the receiving authority. The manufacturer shall keep carrying out manufacturing operations in accordance with principles of GMP.

Article 12. Unexpected inspection of GMP compliance or audit of GMP compliance and maintenance thereof

1. Audit of GMP complianceand maintenance thereof by manufacturers shall be conducted as prescribed by law.

2. An unexpected inspection of GMP compliance and maintenance thereof shall be carried out at the manufacturer in one of the following cases:

a) The result of deficiency rectification by the manufacturer shows it still fails to comply with GMP according to Sub-point 2 Point c Clause 6 Article 11 of this Circular;

b) The manufacturer that complies with GMP at level 3 or level 4 according to Points c and d Clause 3 Article 7 of this Circular shall undergo an unexpected inspection at least once within 03 (three) years from the end of the previous inspection;

c) The manufacturer has at least 01 batch of pharmaceutical products which is recalled because of first-degree violations;

d) The manufacturer has a pharmaceutical product that is reported to have adverse effects, including serious ones;

dd) The inspecting authority concludes that the manufacturer seriously violates GMP;

e) There is any complaint or denunciation that the manufacturer seriously violates GMP;

g) The manufacturer fails to submit the operation and GMP compliance report according to Clause 5 Article 9 of this Circular.

3. The head of the receiving authority shall decide on members of the inspectorate as prescribed in Article 15 of this Circular.

4. Sequence of conducting unexpected inspections at a manufacturer is mentioned in Article 7 of this Circular.

5. Results of unexpected inspections or audits conducted at a manufacturer shall be processed as prescribed by law.

Chapter V

INSPECTION OF GMP COMPLIANCE BY MANUFACTURERS NOT REQUIRED TO OBTAIN CERTIFICATES OF ELIGIBILITY FOR PHARMACY BUSINESS AND OVERSEAS MANUFACTURERS WHEN THEY APPLY FOR REGISTRATION OF PHARMACEUTICAL PRODUCTS AND PHARMACEUTICAL STARTING MATERIALS IN VIETNAM

Article 13. Inspection of GMP compliance by manufacturers not required to obtain certificates of eligibility for pharmacy business

1. A manufacturer not required toobtain the certificate of eligibility for pharmacy business (non-commercial pharmacy establishment) must comply with GMP as prescribed in Point a Clause 2 Article 35 of the Law on Pharmacy.

2. The manufacturer not required toobtain the certificate of eligibility for pharmacy business (except the health facility’s division in charge of pharmaceutical product preparation) shall submit an application form for inspection of GMP compliance using the Form No. 1 in the Appendix X hereof and technical documents about the manufacturer, which shall be prepared in accordance with guidelines for the site master file in the Appendix VIII hereof in case of first inspection or manufacturing operation and GMP compliance report enclosed with updated technical documents about the manufacturer (if any change is made) according Clause 2 of Article 9 in case of periodic inspection.

3. Sequence of inspection and procedures for inspection and classification of results of inspection of GMP compliance, control of changes and unexpected inspection of GMP compliance by manufacturers of pharmaceutical products and pharmaceutical starting materials not required to obtain certificates of eligibility for pharmacy business are mentioned in Articles 6, 7, 9, 11 and 12 of this Circular.

4. Results of first inspection of GMP compliance by a manufacturer of pharmaceutical products and pharmaceutical starting materials not required to obtain the certificate of eligibility for pharmacy business shall be processed as follows:

a) Sequence and time of processing result of first inspection of GMP compliance by the manufacturer are mentioned in Article 8 of this Circular.

b) The receiving authority shall send a notification of status of GMP compliance by the manufacturer and publish it on its website and web portal of the Ministry of Health as prescribed in Clause 6 of this Article.

5. Results of unexpected and periodic inspections of GMP compliance by a manufacturer of pharmaceutical products and pharmaceutical starting materials not required to obtain the certificate of eligibility for pharmacy business shall be processed as follows:

a) If the inspection result shows that the manufacturer complies with GMP at level 1 or level 2 or level 3 as prescribed in Points a, b and c Clause 3 Article 7 of this Circular, the receiving authority shall carry out inspection as prescribed in Clauses 1, 2 and 3 Article 10 of this Circular.

b) If the inspection result shows that the manufacturer complies with GMP at level 4 as prescribed in Point d Clause 3 Article 7 of this Circular, the receiving authority shall carry out an inspection and issue a decision on suspension of all manufacturing operations or manufacturing operations that fail to comply with GMP until the result of deficiency rectification by the manufacturer rectifies is satisfactory.

c) If it is concluded that a sample of pharmaceutical product or pharmaceutical starting material collected by the inspectorate during the inspection violates quality regulations, the receiving authority shall handle it in accordance with applicable regulations on management of quality of pharmaceutical products and pharmaceutical starting materials. The head of the manufacturer shall be responsible to law for such violation.

6. Within 05 working days from the date of concluding that the GMP compliance or maintenance of GMP compliance by a manufacturer of pharmaceutical products and pharmaceutical starting materials not required to obtain the certificate of eligibility for pharmacy business, the receiving authority shall publish the following information on its website and web portal of the Ministry of Health:

a) Name and address of the manufacturer;

b) Full name of the person in charge of pharmacy, person in charge of quality assurance and number of his/her pharmacy practicing certificate;

c) Number of certificate of GMP compliance;

d) Expiry date of inspection of GMP compliance;

dd) Scope of operation of the manufacturer.

e) EU - GMP certificate number, effective period and issuing authority if the manufacturer has its compliance with EU - GMP or equivalent (if any) inspected by SRA.

Article 14. Inspection of GMP compliance by overseas manufacturers when they apply for registration of pharmaceutical products and pharmaceutical starting materials in Vietnam

1. Before submitting an application for inspection of GMP compliance to the Ministry of Health (the receiving authority specified in Clause 1 Article 6 of this Circular) shall have its GMP compliance inspected and certified by a competent pharmacy authority of the home country.

2. Methods, contents, documentation, sequence, procedures and power for inspection of GMP compliance by overseas manufacturers are mentioned in Articles 96, 97, 98 and 99 of the Decree No. 54/2017/ND-CP.

In the cases where the inspection of GMP compliance is conducted using the method for conducting a inspection at the manufacturer, procedures for inspecting, classifying and processing inspection results and controlling changes is prescribed in Articles 6, 7, 8, 9, 10, 11 and 12 of this Circular.

3. Within 10 working days from the date on which the result of inspection of GMP compliance by a manufacturer is obtained, the receiving authority shall publish the following information on its website and web portal of the Ministry of Health:

a) Name and address of the manufacturer;

b) Number of certificate of GMP compliance, GMP documents applied, effective period of certificate of GMP compliance and name of the competent pharmacy authority in the cases specified in Points a and b Clause 5 Article 54 of the Law on Pharmacy or date of GMP compliance inspection by the Vietnam Ministry of Health, GMP documents applied and effective period of result of inspection of GMP compliance in the case specified in Point c Clause 5 Article 54 of the Law on Pharmacy;

c) Scope of operation of the inspected manufacturer.

Chapter VI

INSPECTORATE CONDUCTING INSPECTIONS OF GMP COMPLIANCE

Article 15. Members and standards to be satisfied by members of an inspectorate

1. An inspectorate includes:

a) The chief and 01 or 02 members of the receiving authority. 01 or 02 members of the Traditional Medicine Administration of Vietnam, regarding the manufacturer specified in Point c Clause 1 Article 6 of this Circular;

b) 01 member: the representative of the National Institute of Drug Quality Control or Institute of Drug Quality Control - Ho Chi Minh City or National Institute for Control of Vaccine and Biologicals (regarding the manufacturer of vaccines and biologicals);

c) 01 member: the representative of the Department of Health of a province or central-affiliated city (hereinafter referred to as “the Department of Health”) where the factory is located.

d) Members of relevant authorities where necessary.

2. A member of the inspectorate must satisfy the following standards:

a) He/she must obtain at least a bachelor’s degree and has been provided with training medicine, pharmacy, biology, pharmaceutical product quality management and pharmacy management;

b) He/she has been trained in GMP and inspection of GMP compliance, and has a thorough grasp of GPP principles. Members joining the inspectorate conducting inspections of manufacturers of traditional pharmaceutical products and herbal ingredients must be trained in GMP for traditional pharmaceutical products and herbal ingredients.

c) He/she must be honest, objective strictly comply with regulations during the inspection and must not create any conflict of interest with the inspected manufacturer as prescribed in Clause 3 of this Article;

d) The chief must have at least 03 (three) years’ experience in pharmacy management.

3. Rules for assessing the conflict of interest: A member of the inspectorate shall be deemed to involve a conflict of interest with the inspected manufacturer in one of the following cases:

a) He/she has worked or participated in providing consulting services for the inspected manufacturer in the past 05 years;

b) He/she is receiving financial benefits associated with the inspected manufacturer;

c) His/her spouse, child, parent, sibling or parent-in-law is working for the inspected manufacturer.

Article 16. Rights and responsibilities of an inspectorate

1. The inspectorate has the responsibility to:

a) Inspect all operations of a manufacture according to corresponding GMP prescribed in Article 3 of this Circular, updated versions of GMP principles and relevant legislative documents and regulations; clearly record inspection contents and deficiencies found, prepare GMP inspection records and reports;

b) Report inspection results or provide explanation for the GMP inspection report if the manufacturer has any disagreements with the report;

c) Maintain confidentiality of all information about the inspection and manufacturing operations, inspection of quality, storage and distribution of pharmaceutical products (manufacturing, testing and cleaning process, technological secrets, etc.) unless otherwise agreed upon by the manufacturer or requested by the competent authority.

2. The inspectorate has the right to:

a) Inspect all areas and premises of the manufacturer and request inspection of other areas related to the manufacture, storage and testing of pharmaceutical products and pharmaceutical starting materials. Regarding manufacture of traditional ingredients, inspect the traditional ingredient processing and manufacturing process.

b) Request the manufacturer to provide documents concerning its quality management, manufacture, testing and storage of pharmaceutical products and pharmaceutical starting materials;

c) Collect documentary evidences (by copying documents, taking pictures or recording videos) of deficiencies found during the inspection;

d) Take samples of pharmaceutical products, semi-finished products and herbal ingredients to test their quality as regulated by laws;

dd) Make inspection records and request the manufacturer to suspend one, some or all of its manufacturing operations related to violations. During the inspection, if the inspectorate finds that the manufacturer commits a violation which seriously affects quality of one or multiple pharmaceutical products and pharmaceutical starting materials, it is required to notify the competent person thereof.

Chapter VII

IMPLEMENTATION CLAUSE

Article 17. Effect

1. This Circular takes effect on January 10, 2019.

2. The following documents and regulations are null and void from the effective date of this Circular:

a) Decision No. 3886/2004/QD-BYT dated November 03, 2004 of the Minister of Health;

b) Regulations on GMP specified in the Decision No. 27/2007/QD-BYT dated April 19, 2007 of the Minister of Health;

c) Regulations on GMP specified in the Circular No. 45/2011/TT-BYT dated December 21, 2011 of the Minister of Health; Decision No. 2701/2001/QD-BYT dated June 29, 2001 of the Minister of Health; Circular No. 06/2004/TT-BYT dated May 28, 2004; Decision No. 3886/2004/QD-BYT dated November 03, 2004 of the Ministry of Health; Circular No. 13/2009/TT-BYT September 01, 2009 of the Ministry of Health; Circular No. 22/2009/TT-BYT dated November 24, 2009 of the Ministry of Health; Circular No. 2010/TT-BYT dated December 29, 2010.

d) Regulations on conditions for processing herbal ingredients in the Circular No. 03/2016/TT-BYT dated January 21, 2016 of the Minister of Health shall remain effective until December 31, 2020 according to Clause 4 Article 19 of this Circular.

dd) Regulation: “If the test facility fails to submit the application as prescribed, the Ministry of Health shall revoke its certificate of eligibility for pharmacy business as prescribed in Clause 2 Article 40 of the Law on Pharmacy” specified in Clause 5 Article 9 of the Circular No. 04/2018/TT-BYT of the Minister of Health dated February 09, 2018.

Article 18. Reference clause

In the cases where any of the legislative documents and regulations referred to in this Circular is amended or replaced, the newest one shall apply.

Article 19. Transitional clauses

1. Any manufacturer of pharmaceutical products and pharmaceutical starting materials that has been issued with the certificate for eligibility for pharmacy business that allows manufacture of pharmaceutical products and pharmaceutical starting materials or certificate of GMP compliance before the effective date of this Circular is entitled to manufacture pharmaceutical products and pharmaceutical starting materials until the expiry date of such certificate.

If the certificate of eligibility for pharmacy business expires, the manufacturer shall apply for the certificate of eligibility for pharmacy business as prescribed by law.

If the certificate of GMP compliance expires before the expiry date of the certificate of eligibility for pharmacy business, the manufacturer shall apply for inspection of GMP compliance and maintenance thereof according to Chapter IV of this Circular in order to keep operating as prescribed.

2. Regarding the manufacturer of pharmaceutical products and pharmaceutical starting materials that has been issued with the indefinite term certificate for eligibility for pharmacy business that allows manufacture of pharmaceutical products and pharmaceutical starting materials, it shall, upon the expiry date of the certificate of GMP compliance, apply for inspection of GMP compliance and follow relevant procedures as prescribed by law.

3. Regarding applications for certificate of eligibility for pharmacy business or applications for periodic inspection of GMP compliance submitted to the receiving authority before the effective date of this Circular, the receiving authority shall keep inspecting the manufacturer according to GMP promulgated together with the Decision No.  3886/2004/QD-BYT dated November 03, 2004 of the Minister of Health or regulations of this Circular if the manufacturer so requests.

4. If an herbal ingredient trading establishment that processes herbal ingredients has had its GMP compliance inspected and published by the Traditional Medicine Administration of Vietnam on the web portal as prescribed in the Circular No. 03/2016/TT-BYT dated January 21, 2016 of the Minister of Health shall keep operating until December 31, 2020. By January 01, 2021, every establishment manufacturing and processing herbal ingredients and traditional ingredients shall submit an application for the certificate of eligibility for pharmacy business that allows processing of herbal ingredients and manufacture of traditional ingredients as prescribed in Article 5 of this Circular and comply with manufacturing conditions prescribed in Articles 13, 14, 15, 16, 17, 18, 19 and 20 of the Circular No. 03/2016/TT-BYT dated January 21, 2016 of the Minister of Health. Documentation and procedures for conducting inspections and processing inspection results are mentioned in Articles 5, 6, 7 and 8 of this Circular.

Article 20. Responsibility for implementation

1. The Drug Administration of Vietnam shall:

a) Take charge and cooperate with relevant units in organizing the dissemination of this Circular. Take charge of compiling a list of GMP criteria relevant to each type of manufacturing according to the principle of transparency, clarity and accuracy and request the Ministry of Health to promulgate it to form a basis for application of GMP to manufacturers of pharmaceutical products and pharmaceutical starting materials and inspection by pharmacy authorities.

b) Within its jurisdiction, instruct Provincial Departments of Health, health authorities and manufacturers of pharmaceutical products and pharmaceutical starting materials to implement this Circular;

c) Consolidate and publish the list of manufacturers that have been granted the certificate of eligibility for pharmacy business and/or Certificate of GMP compliance, status of such certificates, status of GMP compliance and other information on its website according to Clause 6 Article 8 of this Circular within its jurisdiction;

d) Publish updated GMP documents on its website and the web portal of the Ministry of Health;

dd) Take charge or cooperate with the Ministry Inspectorate in inspecting and auditing GMP compliance and take actions against violations within its power.

2. The Traditional Medicine Administration of Vietnam shall:

a) Within its jurisdiction, instruct Provincial Departments of Health, health authorities and manufacturers of pharmaceutical products and pharmaceutical starting materials to implement this Circular;

b) Consolidate and publish the list of manufacturers that have been granted the certificate of eligibility for pharmacy business or Certificate of GMP compliance, status of such certificates, status of GMP compliance and other information on its website according to Clause 6 Article 8 of this Circular within its jurisdiction;

c) Take charge or cooperate with the Ministry Inspectorate in inspecting and auditing GMP compliance and take actions against violations within its power.

3. Provincial Departments of Health shall:

a) Cooperate with relevant units in organizing the dissemination of this Circular and instruct units within provinces to implement this Circular;

b) Join the inspectorate conducting inspections of GMP compliance; within their power, supervise and takes actions against violations against regulations on GMP compliance by manufacturers of pharmaceutical products and pharmaceutical starting materials within provinces.

4. The National Institute of Drug Quality Control, Institute of Drug Quality Control - Ho Chi Minh City and National Institute for Control of Vaccine and Biologicals shall join the inspectorate conducting inspections of GMP compliance upon request.

5. Manufacturers of pharmaceutical products and pharmaceutical starting materials shall:

a) Organize the implementation of this Circular;

b) Ensure their compliance with GMP during their operation;

c) Carry out manufacturing operations within the inspected and licensed scope according to regulations of law.

Difficulties that arise during the implementation of this Circular should be reported to the Ministry of Health (Drug Administration of Vietnam or Traditional Medicine Administration of Vietnam) for consideration./.

For the Minister

The Deputy Minister

Truong Quoc Cuong