CIRCULAR

AMENDMENTS TO AND ABROGATION OF SOME LEGISLATIVE DOCUMENTS PROMULGATED OR JOINTLY PROMULGATED BY THE MINISTER OF HEALTH

Pursuant to the Law on Promulgation of Legislative Documents dated June 22, 2015 and the Law dated June 18, 2020 on Amendments to the Law on Promulgation of Legislative Documents;

Pursuant to the Law on Pharmacy dated April 06, 2016;

Pursuant to the Law on Tobacco Harm Prevention and Control dated June 18, 2012;

Pursuant to the Government's Decree No. 54/2017/ND-CP dated May 08, 2017 on elaboration of the Law on Pharmacy;

Pursuant to the Government's Decree No. 69/2018/ND-CP dated May 15, 2018 on elaboration of the Law on Foreign Trade Management;

Pursuant to the Government's Decree No. 96/2012/ND-CP dated November 15, 2012 on opioid substitution therapy;

Pursuant to the Government's Decree No. 15/2018/ND-CP dated February 02, 2018 on elaboration of the Law on Food Safety;

Pursuant to the Government's Decree No. 34/2016/ND-CP dated May 14, 2016 on elaboration of the Law on Promulgation of Legislative Documents;

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

At the request of the Director of the Legal Department,

The Minister of Health promulgates a Circular on amendments to and abrogation of some legislative documents promulgated or jointly promulgated by the Minister of Health.

Article 1. Amendments to some legislative documents on cosmetics, pharmacy, prevention and control of HIV/AIDS, and food safety

1. Amendments to some Articles of Circular No. 06/2011/TT-BYT dated January 25, 2011 of the Minister of Health on cosmetics management (hereinafter referred to as “Circular No. 06/2011/TT-BYT")

a) Clause 4 Article 4 is amended as follows:

“4. Certificate of Free Sale (CFS) of imported cosmetic products:

a) Cases of CFS exemption:

- The cosmetic products are manufactured in a member country of the Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP) the participation in which has been approved and brought into effect by competent authorities of that country;

- The cosmetics products are marketed in and exported from a CPTPP member country: The enterprise responsible for marketing of the products shall submit documents proving that the products have been marketing in the CPTPP member country that are issued by competent authorities of the same country (marketing authorization or registered cosmetic product notification or other documents certifying the marketing of the products in the country) and consularly legalized as prescribed by law, unless:

+ These documents are exempt from consular legalization under an international treaty to which the Socialist Republic of Vietnam (hereinafter referred to as “Vietnam”) is a signatory or under principle of reciprocity between Vietnam and the issuing country;

+ A diplomatic authority, cosmetics management authority or issuing authority of the CPTPP country sends a physical document or email to Drug administration of Vietnam to certify these documents;

+ The enterprise responsible for marketing of the products obtains these documents from the website (in English) of the issuing authority of the CPTPP member country which bear the seal of the enterprise and sends it together with the link to that website to Drug Administration of Vietnam. The enterprise shall be legally responsible for the legitimacy and accuracy of these documents and information;

- The cosmetics products have been granted a product notification number in an ASEAN country, in which case the enterprise responsible for marketing of the products shall submit the cosmetic product notification which is consularly legalized, unless:

+ The cosmetic product notification is exempt from consular legalization under an international treaty to which Vietnam is a signatory or under principle of reciprocity between Vietnam and the issuing country;

+ A diplomatic authority, cosmetics management authority or issuing authority of the ASEAN country sends a physical document or email to Drug administration of Vietnam to certify the cosmetic product notification;

+ The enterprise responsible for marketing of the products obtains the cosmetic product notification from the website (in English) of the issuing authority of the CPTPP member country which bears the seal of the enterprise and sends it together with the link to that website to Drug Administration of Vietnam. The enterprise shall be legally responsible for the legitimacy and accuracy of these documents and information;

b) Except for the cases of CFS exemption specified in Point a of this Clause, the application for notification of imported cosmetic products shall have a CFS that satisfies the following requirements:

- The CFS is still effective and issued by a competent authority of the country or origin or exporting country (original copy or authenticated copy). In case the CFS does not have an expiration date, it must be issued within the last 24 months;

- The CFS is consularly legalized as prescribed by law, unless:

+ Consular legalization is exempt under an international treaty to which Vietnam is a signatory or under principle of reciprocity between Vietnam and the issuing country;

+ The issuing authority or a diplomatic authority sends a physical document or email to Drug Administration of Vietnam to certify the CFS;

- The CFS contains at least the information specified in Article 36 of the Law on Foreign Trade Management and Clause 3 Article 10 of the Government's Decree No. 69/2018/ND-CP dated May 15, 2018 on elaboration of the Law on Foreign Trade Management (hereinafter referred to as “Decree No. 69/2018/ND-CP).”;

b) Appendix No. 01-MP enclosed with Circular No. 06/2011/TT-BYT is amended by Appendix 1 hereof;

c) Article 33 is amended as follows:

“Article 33. Procedures and application for CFS for export of domestically manufactured cosmetic products

1. The application for CFS for export of domestically manufactured cosmetic products shall be prepared in accordance with Article 11 of Decree No. 69/2018/ND-CP. The document about applied standards may be replaced with the registered cosmetic product notification (01 copy bearing the trader’s seal).

2. The procedures for issuance of the CFS for export of cosmetic products are specified in Article 11 of Decree No. 69/2018/ND-CP.

3. The fee for issuance of the CFS shall be charged for the quantity of products on 01 product notification number issued.

4. Provincial Departments of Health shall issue and manage CFS for export of cosmetic products manufactured in their provinces.”.

2. Appendix VII of Circular No. 20/2017/TT-BYT is amended as follows:

The following text is added to the end of Appendix VII (List of drugs and active ingredients banned from certain fields): “This List includes all salts (if any) of the substances specified in herein.”.

3. Point dd Clause 2 Article 17 of Circular No. 02/2018/TT-BYT is amended as follows:

“dd) Upload quarterly reports on the list of pharmacies in the province which have been granted Certificates of eligibility for pharmacy business, and their degrees of fulfillment of GPP requirements as prescribed in Clause 4 Article 8 herein to the website of Drug Administration of Vietnam.”.

4. Point dd Clause 3 Article 18 of Circular No. 03/2018/TT-BYT on good distribution practice is amended as follows:

“dd) Monthly upload the list of local distributors that have been issued with the certificate of eligibility for pharmacy business and status of GDP compliance according to Clause 4 Article 8 of this Circular to website of the Drug Administration of Vietnam.”.

5. Amendments to Circular No. 32/2018/TT-BYT dated November 12, 2018 on registration of drugs and medicinal ingredients (hereinafter referred to as “Circular No. 32/2018/TT-BYT"):

a) Point c Clause 3 Article 23 is amended as follows:

“c) If an electronic document does not bear the signature, full name of the signer and seal of the competent authority of the issuing country, the applicant shall submit one of the following documents:

- Consularly legalized documents (original copies or authenticated copies);

- The applicant shall send the legal documents that are downloaded from the English website of the issuing authority and bear the confirmation seal of the applicant together with a document specifying the download links to Drug Administration of Vietnam. The applicant shall be legally responsible for the legitimacy and accuracy of these documents and information.”;

b) Point c Clause 4 of Article 23 is abrogated;

c) Point e and Point g Clause 4 of Article 23 are amended as follows:

“e) An application for marketing authorization of new modern drugs, imported biologics other than probiotics shall have a CPP issued by a competent authority of the manufacturing country with a confirmation that the drug is licensed and marketed in that country in reality. In case the CPP is not issued by EMA, legal documents issued by one of the regulatory authorities specified in Clause 9 or Clause 10 Article 2 of this Circular. The legal documents shall contain at least the following information: drug name, active ingredients and their concentration or content, dosage form, name and address of the manufacturing facility, confirmation that the drug is licensed and marketed in that country in reality;

g) An application for marketing authorization of an imported vaccine shall have a CPP issued by a competent authority of the manufacturing country with a confirmation that the drug is licensed and marketed in that country in reality. In case the CPP is not issued by EMA, legal documents issued by one of the regulatory authorities specified in Clause 9 or Clause 10 Article 2 of this Circular. The legal documents shall contain at least the following information: drug name, active ingredients and their concentration or content, dosage form, name and address of the manufacturing facility, confirmation that the drug is licensed and marketed in that country in reality;

d) Point dd below is added to Clause 12 of Article 23:

“dd) For excipients in the application for registration of finished drugs/semi-finished medicinal ingredients:

If the documents specified in Point a, b, d of this Clause cannot be provided, the manufacturer of the finished drugs/semi-finished medicinal ingredients shall carry out self-assessment of its good manufacturing practice in accordance with Point dd Clause 1 Article 3, Point b Clause 3 Article 3 and Point dd Clause 5 Article 20 of Circular No. 35/2018/TT-BYT and make a self-declaration of GMP and take legal responsibility for such declaration according to Form 13/TT enclosed herewith”;

dd) Clause 3 of Article 40 is amended as follows:

“3. Minor variations that only require notification:

a) For minor variations that only require notification (MiV-N1, MiV-N2, MiV-N3, MiV-N4, MiV-N6, MiV-N7) specified in Appendix II hereof: The authorization holder shall take responsibility for these variations from the date written on the receipt note. Within 15 working days from the date written on the receipt note, Drug Administration of Vietnam shall update these minor variations to its website;

b) For minor variations that only require notification other than those mentioned in Point a of this Clause: Within 15 working days from the date written on the receipt note, Drug Administration of Vietnam shall approve these variations and update the marketing authorization if the application is satisfactory, or make a written response and provide explanation if the application is not satisfactory; update these minor variations to the website of Drug Administration of Vietnam and inform the applicant.”;

e) The title of Clause 2 Article 47 is changed as follows: “2. Effective periods of marketing authorizations that expire during the period from January 01, 2018 to December 31, 2021, including those that have their effect maintained, will be extended for 12 more months if all of the following requirements are satisfied:”

g) Clause 5 below is added to Article 47:

“5. Effect of GMP certificates:

a) For GMP certificates issued by pharmacy authorities of countries in European Economic Area (EEA):

- GMP certificates that are extended under EMA’s Notice dated April 10, 2020 regarding policies on drugs for human use during Covid-19-19 pandemic will be effective until December 31, 2021. In case EMA issues a new notice, the newer one shall prevail;

- In case a new GMP certificate has been issued, the effective period of the new certificate shall apply;

b) For GMP certificates that are not issued by the authorities mentioned in Point a of this Clause, their effective periods during Covid-19 pandemic shall comply to notices of pharmacy authorities of each country in which these GMP certificates are issued, or shall be the effective periods specified in these certificates.”;

h) Clause 3 of Article 48 is amended as follows:

“3. Regarding applications for renewal or revision of the marketing authorization submitted before December 31, 2021: specifications of the drug product, active ingredients, herbal ingredients, name and address of manufacturers thereof are not requirements in the CPP.”;

i) Clause 5 and Clause 6 below are added to Article 48 as follows:

“5. For domestically manufactured drugs/medicinal ingredients whose marketing authorizations have been granted before December 31, 2020, if the authorization holder wishes to import medicinal ingredients that are excipients or capsule shells into Vietnam: Before the first import, the authorization holder shall update the information about medicinal ingredients that are excipients or capsule shells in the approved application to the online public service system of Drug Administration of Vietnam. Within 05 working days from the day on which the update is completed, Drug Administration of Vietnam shall complete the announcement process. The applicant shall be held responsible for the accuracy of the updates and is not required to update information upon the next import.

6. Regulations on authentication of legal documents in applications for issuance, renewal, revision of the marketing authorization submitted before December 31, 2021: It is not mandatory to have the result of authentication of legal documents prescribed in Clause 1 Article 12 of this Circular before the date of issuance, renewal or revision unless the legal documents are electronic files that do not satisfy the requirements specified in Clause 1, Point a and Point b Clause 3 Article 23 of this Circular, in which case the result of authentication of these legal documents is required before the date of issuance, renewal or revision.

In case a diplomatic authority or a competent authority of Vietnam or the foreign country issues a document to disprove the authenticity of the legal documents in the application, Drug Administration of Vietnam shall consider handling the case in accordance with Clause 5 Article 42 and Point h Clause 1 Article 50 of this Circular.”;

k) Point o below is added to Clause 1 of Article 50:

“o) Publish the list of website of issuing authorities of the legal documents specified in Point c Clause 3 Article 23 of this Circular.”;

l) Form No. 13/TT “Declaration of application of GMP principles for excipients applied by other international organizations or foreign regulatory authorities” in Appendix 2 hereof is added to Circular No. 32/2018/TT-BYT.

6. Amendments to Circular No. 35/2018/TT-BYT dated November 22, 2018 of the Minister of Health on good manufacturing practice for pharmaceutical products and pharmaceutical starting materials (medicinal ingredients):

a) Clause 1 Article 3 is amended as follows:

“1. The following GMP principles shall be applied:

a) WHO GMP principles provided in the Appendix I hereof and updated documents specified in Clause 4 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 4 of this Article;

c) GMP principles of Pharmaceutical Inspection Co-operation Scheme provided in the Appendix I hereof and updated documents specified in Clause 4 of this Article;

d) EU - GMP principles provided in the Appendix IV hereof and updated documents specified in Clause 4 of this Article.

dd) WHO GMP principles for medicinal ingredients that are excipients listed in Appendix IIa hereof and the updated documents specified in Clause 4 of this Article.”;

b) Clause 3 of Article 3 is amended as follows:

“3. Application of other GMP principles:

a) For manufacturers of drugs and medicinal ingredients other than excipients:

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 may be applied. Manufacturers of drugs and medicinal ingredients that apply these GMP principles shall produce and certify translations in accordance with regulations of law on notary and authentication; send these transactions to Drug Administration of Vietnam for uploading onto its website and the website of the Ministry of Health;

b) For manufacturers of excipients:

In addition to the GMP principles mentioned in Point dd Clause 1 of this Article, manufacturers of may apply other GMP principles of International Pharmaceutical Excipients Council (IPEC), the Certification Scheme for Pharmaceutical Excipients (EXCiPACT), American National Standards Institute (ANSI), United States Pharmacopeia (USP) or other principles for manufacture of excipients applied by other excipient-related international organizations or foreign regulatory authorities.";

c) Clause 16 below is added to Article 4:

“16. Manufacturers of excipients shall apply GMP principles and regulations of Appendix IIa hereof or other GMP principles mentioned in Clause 3 Article 3 of this Circular and updated documents mentioned in Clause 4 Article 3 of this Circular. In case WHO, IPEC, EXCiPACT, ANSI, USP or other international organizations relevant to excipients used for manufacture of drugs, cosmetics, foods publish updates to their GMP principles (hereinafter referred to as “updated documents”) on their websites, manufacturers of excipients shall apply the updated documents within:

a) 12 months in case of any change of premises or manufacturing equipment, from the date on which updated documents are published;

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.”;

d) Point h below is added to Clause 2 of Article 12:

“h) The manufacturer produces medicinal ingredients that are excipients.”;

dd) Point dd below is added to Clause 5 of Article 20:

“dd) Manufacturers of drug products and semi-finished products shall, on the basis for the purposes and uses of the excipients at the manufacturing facility, carry out self-assessment of compliance to GMP principles specified in Point dd Clause 1 Article 3 and Point b Clause 3 Article 3 of this Circular regarding the recipients used at the facility.”;

e) Appendix 3 hereof (Good Manufacturing Practices: Pharmaceutical excipients) is added as Appendix IIa after Appendix II of Circular No. 35/2018/TT-BYT.

7. Clause 6 Article 9 of Circular No. 36/2018/TT-BYT dated November 22, 2018 on good storage practices (GSP) for pharmaceutical products and pharmaceutical starting materials is amended as follows:

“6. After submitting the operation and GSP compliance report within the prescribed time limit, the storage facility is entitled to carry on the business operations specified in the certificate for eligibility for pharmacy business until the result of periodic inspection of GSP compliance is available and shall maintain the GSP compliance throughout its operation.".

8. Amendments to Circular No. 15/2019/TT-BYT dated July 11, 2019 of the Minister of Health on drug biddings at public health facilities:

a) Clause 3 Article 7 is amended as follows:

“3. Category 3 includes drugs that are granted marketing authorization or license for import for marketing in Vietnam and have bioequivalence reports published by Drug Administration of Vietnam.”;

b) Clause 5 of Article 7 is amended as follows:

“5. Category 5 includes drugs that are granted marketing authorization or licenses for import for marketing in Vietnam.”;

c) Point a Clause 8 of Article 50 is amended as follows:

“a) Legal documents issued by pharmacy authorities of SRA countries. These documents must bear full names and signatures of the signers and seals of the competent authorities of the countries and be consularly legalized (original copies or certified true copies).

In case of electronic legal documents, including those without signers’ full names and signatures and seals of the competent authorities, the applicant shall send the documents obtained from English website of the issuing authority to Drug Administration of Vietnam. These documents shall bear the applicant’s seal and be enclosed with a document containing the download links. The applicant shall be legally responsible for the legitimacy and accuracy of these documents.

The legal documents shall have the following contents: drug name, active ingredients, their concentration or content, dosage form, name and address of the manufacturing facility, certification that the drug is approved for market authorization in that country.”;

d) Appendix No. 3 of Circular No. 15/2019/TT-BYT is amended by Appendix 4 hereof;

dd) Clause 1 of Section 1 and Clause 13 of Section II Part 4 of Appendix 7 and Appendix 8 of Circular No. 15/2019/TT-BYT are amended by Appendix 5 hereof.

9. Point a Clause 2 Article 14 of Circular No. 14/2015/TT-BYT dated June 25, 2015 on methadone management is amended as follows:

“a) The methadone dose must be taken in the presence of a health worker, unless methadone is provided by the health facility for home use as instructed by the Ministry of Health;”.

10. Amendments to Circular No. 18/2019/TT-BYT dated July 17, 2019 of the Minister of Health on good manufacturing practice (GMP) for health supplements:

a) Clause 3 Article 3 is amended as follows:

“3. Any manufacturer of herbal medicinal products and traditional medicinal products that has been issued with the effective Certificate of compliance with GMP for herbal medicinal products and traditional medicinal products by the Drug Administration of Vietnam - the Ministry of Health or the Traditional Medicine Administration of Vietnam - the Ministry of Health in accordance with regulations of law on pharmacy is entitled to manufacture health supplements whose dosage forms are equivalent to those that have been certified and is not required to apply for issuance of the Certificate of GMP compliance with health supplements.”;

b) The title of Clause 1 of Article 4 is amended as follows:

“1. Imported health supplements shall be manufactured by a manufacturer that has been granted one of the following certificates or confirmations by a competent authority of the manufacturing country (including food safety regulator or organization designated or acknowledged by the food safety regulator or another country’s organization acknowledged by the regulatory authority of the manufacturing country):”;

c) Point a Clause 1 of Article 4 is amended as follows:

“a) Certificate of GMP compliance if it is a manufacturer of health supplements or Certificate of Free Sale (CFS) stating that the product is manufactured by a GMP-compliant facility;”;

d) Point c Clause 1 of Article 4 is amended as follows:

“c) Regarding the countries or territories that do not issue the certificates specified in Points a and b of this Clause, the manufacturer of health supplements need to obtain a written confirmation that the GMP certificate is not issued in such countries from a competent authority or on the official website of a competent authority;”;

dd) Clause 2 of Article 4 is amended as follows:

“2. A certificate or confirmation mentioned in Points a and b Clause 1 of this Article (except CFS with the contents specified in Point a Clause 1 of this Article) shall contain:

a) Name of the issuing authority;

b) Date of issue;

c) Expiration date (if the expiration date is not written on the certificate or confirmation, an assessment report or periodic inspection record are required to prove that the manufacturer still maintains its fulfillment of food safety conditions, or the assessment/inspection time must be provided for by legislative documents of the country of origin);

d) Full name and signature of the person issuing the certificate;

dd) Name and address of the certificate holder;

e) Scope covered by the certificate.”;

e) Clause 2 Article 5 and the paragraph “The provisions of this Clause shall come into force on the effective dates of the legislative documents mentioned in Clause 2 Article 5 of this Circular” in Point b Clause 1 Article 4 are abrogated.

g) Paragraph 3.7 of Section III of the Appendix of Circular No. 18/2019/TT-BYT is amended as follows:

“3.7. In case the health supplements, herbal medicines and traditional medicines are manufactured by the same line, appropriate measures must be taken to prevent confusion and cross-contamination (refer to section 6.19).”.

11. The paragraph “Regulations on maximum permissible contents of tar and nicotine specified in QCVN 16-1:2015/BYT are effective until December 31, 2020” in Article 2 of Circular No. 23/2015/TT-BYT dated August 20, 2015 promulgating the National technical regulation for cigarette is amended as follows:

“Regulations on maximum permissible contents of tar and nicotine specified in QCVN 16-1:2015/BYT will be reviewed every 02 years and adjusted where necessary”.

Article 2. Abrogation of some legislative documents promulgated or jointly promulgated by the Minister of Health

28 legislative documents promulgated or jointly promulgated by the Minister of Health specified in Appendix 6 hereof are abrogated.

Article 3. Effect

1. This Circular comes into force from February 15, 2021.

2. Regulations of Clauses 5, 6, 7, 8 and 11 Article 1 of this Circular come into force from January 1, 2021.

3. Regulations on online submission and access of documents shall apply during Covid-19 pandemic until revised by the Ministry of Health.

Article 4. Transition clauses

1. The documents that are submitted before the effective date of this and are still processed will apply relevant regulations of this Circular or the regulations that are effective before the effective date of this Circular, whichever is more convenient for enterprises, organizations and individuals.

2. Regulations of this Circular on online publishing, update, declaration and reporting of information shall be applied as instructed by competent authorities.

Article 5. Responsibility for implementation

Director of the Legal Department, the Chief of the Ministry Office, the Ministerial Chief Inspector, Directors of Departments of the Ministry of Health, relevant organizations and individuals are responsible for the implementation of this Circular./.

APPENDIX 2

(Promulgated together with Circular No. 29/2020/TT-BYT dated 31/12/2020 of the Minister of Health)

Form No. 13/TT

DECLARATION OF COMPLIANCE TO GMP REGULATIONS OR OTHER REGULATIONS/STANDARDS FOR MANUFACTURE OF EXCIPIENTS APPLIED BY OTHER INTERNATIONAL ORGANIZATIONS OR FOREIGN REGULATORY AUTHORITIES

<Name of manufacturer>

Is the manufacturer of the drug or semi-finished medicinal ingredient below:

Name of drug product/semi-finished medicinal ingredient:

Active ingredients, content/concentration:

Dosage form:

Which has been granted marketing authorization by the Ministry of Health (Drug Administration of Vietnam) of Vietnam.

On the basis of the purposes and uses of excipients in the formula in the manufacture of the finished drug product or medicinal ingredient;

On the basis of our assessment of risks and impacts of the excipients to safety of users, dosage form, manufacturing process and evaluation of ingredient suppliers,

We hereby declares that the following excipients manufactured in our facility comply to GMP regulations or other regulations/standards for manufacture of excipients applied by other international organizations or foreign regulatory authorities prescribed in Point dd Clause 12 Article 23 of Circular No. 32/2018/TT-BYT and are suitable for the purposes of manufacture of the drug product or medicinal ingredient:

We are legally individual this declaration./.

APPENDIX 3

(Promulgated together with Circular No. 29/2020/TT-BYT dated 31/12/2020 of the Minister of Health)

APPENDIX IIA

GOOD MANUFACTURING PRACTICES: PHARMACEUTICAL EXCIPIENTS
(The Ministry of Planning and Investment Circular No. 35/2018/TT-BYT dated November 22, 2018 of the Minister of Health)

TABLE OF CONTENTS

1. General considerations

2. Glossary

3. Self-inspection and quality audit

4. Equipment

4.1. Use of equipment

4.2. Cleaning programme

4.2.1. Detailed cleaning procedure

4.2.2. Sampling plan

4.2.3. Analytical methods/cleaning limits

5. Materials

5.1. General

5.2. Starting materials

5.3. Rejected and recovered materials

5.4. Returned excipients

5.5. Storage practices

6. Documentation

6.1. General

6.2. Specifications

6.3. Batch production records

6.4. Other documents

7. Good practices in production and quality control

7.1. Change control and process validation

7.2. Good practices in production

7.2.1. Prevention of cross-contamination

7.2.2. In-process blending/mixing

7.2.3. Control of microbial contamination

7.2.4. Water systems/water quality

7.2.5. Packaging operations

7.2.6. Delivery

7.3. Good practices in quality control

7.3.1. General

7.3.2. Control of starting materials

7.3.3. In-process testing

7.3.4. Quality records and retention samples

7.3.5. Stability studies

7.3.6. Expiry/re-evaluation dating

7.3.7. Calibration of measuring and test equipment

1. General considerations

These guidelines, which focus on aspects of good manufacturing practices (GMP) specific for pharmaceutical excipients, supplement the general GMP guidelines for pharmaceutical products published by WHO. They also incorporate some of the concepts for quality management systems determined by the International Organization for Standardization (ISO).

Excipients significantly affect the finished product quality, in some cases making up almost the entire formulation. Many pharmaceutical excipients are used in much greater quantities in other industries such as the food, cosmetic or industrial chemical industry. Consistency and rigour of product specifications may not be as critical in these industries as they are for pharmaceuticals, and many of the excipients used are highly variable . Therefore, a programme must be in place which will monitor these excipients and provide the necessary assurance that they meet the quality parameters for pharmaceutical manufacturing processes. The purpose of this document is to lay out some criteria which may be used to achieve this level of assurance.

The formulator of the finished dosage form is highly dependent on the excipient manufacturer to provide bulk substances that are uniform in chemical and physical characteristics. This is particularly important in the product approval process, where bioequivalence comparisons are made between clinical bioequivalence (“biobatch”) production and commercial scale-up batches. To provide adequate assurance of drug product performance in vivo, the excipient used to manufacture commercial batches should not differ significant from what used in biobatches. Where significant differences may be expected, additional testing by the finished dosage manufacturer may be required to establish the bioequivalence of the finished product. It remains equally important to ensure that the bioequivalence of the subsequent, post-approval commercial batches of drug products is not adversely affected over time.

In general, excipients are used as purchased, with no further refinement or purification. Consequently, impurities present in the excipient will be carried over to the finished dosage form. While dosage form manufacturers may have a limited control over excipient quality (i.e. by obtaining certificates of analysis and testing representative samples), the excipient manufacturer has greater control over physical characteristics, quality and the presence of trace-level impurities in the excipients. The excipient manufacturer should perform periodic performance trend analyses of processes, and the purchaser of the material should also maintain a trend analysis of all testing done on the excipient upon receipt.

In the manufacture of excipients, the environmental conditions, equipment and operational techniques employed reflect the chemical industry rather than the finished drug manufacturing industry. In some processes chemical and biochemical mechanisms have not been fully characterized; therefore, the methods and procedures for materials accountability will often differ from those applicable to the manufacture of finished dosage forms. Many chemical processes are performed in closed systems that tend to provide protection against contamination, even when the reaction vessels are not enclosed in buildings. However, this does not preclude the introduction of contaminants from equipment, materials used to protect equipment, corrosion, cleaning and personnel.

Some excipient manufacturing processes may require observance of GMP applicable to finished drug products or bulk active ingredients because of the excipient’s intended use. However, such observance is neither feasible nor necessary in many processes, particularly during the early processing steps. The requirements increase as the process progresses. At some logical processing step, usually well before the final finishing operation, appropriate GMP should be imposed and maintained throughout the remainder of the process. To determine the processing step at which these GMP should be implemented, good judgment and a thorough knowledge of the process are required. A detailed process flow should identify the unit operations, equipment used, stages at which various substances are added, key steps in the process, critical parameters (time, temperature, pressure, etc.) and monitoring points.

An excipient manufacturer should be able to identify critical or key points in the process where selective intermediate sampling and testing is necessary in order to monitor process performance. Towards the end of the process, the records should be increasingly thorough.

Significant processing steps, required to produce an excipient that meets the established physical and chemical criteria, should be identified by the excipient manufacturer. These steps can involve a number of unit operations or unit processes. Unit operations include physical processing steps involving energy transfer where there is no chemical change of the molecule. Unit processes are those processing steps where the molecule undergoes a chemical change.

Significant processing steps include but are not limited to the following:

- Phase changes involving either the desired molecule, a solvent, inert carrier or vehicle (e.g. dissolution, crystallization, evaporation, drying, sublimation, distillation or absorption).

- Phase separation (e.g. filtration or centrifugation).

- Chemical changes involving either the desired molecule (e.g. removal or addition of water of hydration, acetylation, formation of a salt).

- Adjustments of the solution containing the molecule (e.g. adjustment of pH).

- Precision measurement of added excipient components, in-process solutions, recycled materials (e.g. weighing, volumetric measuring).

- Mixing of multiple components.

- Changes that occur in the surface area, particle size or batch uniformity (e.g. milling, agglomeration, blending).

Automated process controls and processing equipment are more likely to be used in an excipient plant than in a plant manufacturing finished dosage forms. Use of automated equipment is appropriate when adequate inspection, calibration and maintenance procedures are performed. Production equipment and operations will vary depending on the type of excipient being produced, the scale of production, and the type of operation (i.e. batch versus continuous).

ISO “certification” for excipient manufacture is increasingly being required by final dosage formulators in the USA, Europe and Japan. Compliance to ISO 9000 series, in particular to ISO 9002, can confer greater acceptability of a supplier’s excipients in world markets. There is additional value to applying the principles of ISO 9000 to excipient manufacture, since quality system measures enhance GMP. Such ISO considerations as conformance to specific customer requirements, purchase of raw materials and statistical techniques benefit both the excipient customer and the manufacturer, and strengthen the relationship between the two.

It is therefore recommended that excipient manufacturers establish and implement a formal company-wide quality policy. Management should be committed to this policy and should appoint appropriate company personnel to be responsible for coordination and implementation of the quality system. Management should participate in the development of the company’s quality policy and provide the resources necessary for development, maintenance and periodic review of such a policy and quality system. Any significant changes in the processes should be validated with respect to excipient performance. It is recommended that all pharmaceutical manufacturers and also local agents should be informed of these changes. Ideally, excipient manufacturers should not subcontract any part of their process without the explicit knowledge of the pharmaceutical manufacturer.

Safe handling instructions should be provided by the excipient manufacturer to ensure that the purchaser is adequately equipped to handle the material. This should include information on the material’s toxicity and the measures to be taken upon accidental exposure. The equipment requirements for proper handling of the material should also be established.

2. Glossary

The definitions given below apply to the terms used in these guidelines.

They may have different meanings in other contexts.

* commingling

The blending of carry-over material from one grade of an excipient with another, usually due to a continuous process.

* drug master file (exclusively applied to regulations of USA)

Detailed information concerning a specific facility, process or product submitted to the drug regulatory authority, intended for incorporation into the application for marketing authorization.

* model product

A product which simulates a group of similar products.

* mother liquor

A concentrated solution from which the product is obtained by evaporation, freezing and/or crystallization.

* pharmaceutical excipients

Substances other than active ingredient , which have been appropriately evaluated for safety and are included in a drug delivery system to:

- Aid in the processing of the drug delivery system during its manufacture;

- Protect, support or enhance stability, bioavailability, or patient acceptability;

- Assist in product identification; or

- Enhance any other attribute of the overall safety and effectiveness of the drug during storage or use.

3. Self-inspection and quality audit

An inspection team consisting of appropriate personnel (e.g. auditors, engineers, laboratory analysts, purchasing agents, computer experts) should participate in inspections. The operational limitations and validation of the critical processing steps of a production process should be examined, to make sure that the manufacturer is taking adequate steps to check that the process works consistently.

The exicpient’s end use should be identified and considered during inspection of excipient manufacturers. It is particularly important to know whether the excipient is a direct or indirect component of a drug dosage form; whether the excipient will be used in the preparation of a sterile dosage form; and whether the excipient is presented as pyrogen/endotoxin free. The excipient manufacturer is responsible for ensuring that the excipients are pyrogen free if the manufacturer makes such a representation in specifications, labels or a drug master file.

A good starting point for an excipient plant inspection is a review of the following areas:

- Non-conformance, such as the rejection of a batch not complying with specifications, return of a product by a customer, or recall of a product. The cause of non-conformance should have been determined by the manufacturer, a report of the investigation prepared, and subsequent corrective actions initiated and documented. Records and documents should be reviewed to ensure that such non-conformance is not the result of a poorly developed or inconsistent process.

- Complaint files. Customers may report some aspects of product attributes that are not entirely suitable for their use. These may be caused by impurities or inconsistencies in the excipient manufacturing process.

- Change control documentation.

- Master formula and batch production records. Frequent revisions may reveal problems in the production process.

- Specifications for the presence of unreacted intermediates and solvent residues in the finished excipient.

- Storage areas for rejected products.

In evaluating the adequacy of measures taken to preclude contamination of materials in the process, it is appropriate to consider the following factors:

- Type of system (e.g. open or closed). “Closed" systems in chemical plants are often not closed when they are being charged and/or when the final product is being removed. Also, the same reaction vessels are sometimes used for different reactions.

- Form of the material (e.g. wet or dry)

- Stage of processing and use of the equipment and/or area (e.g. multipurpose or dedicated)

Other factors that should be considered in evaluating an excipient plant are:

- Degree of exposure of the material to adverse environmental conditions.

- Relative ease and thoroughness of clean-up.

- Sterile versus non-sterile operations.

4. Equipment

4.1. Use of equipment

Many excipients are produced using multipurpose equipment. Fermentation tanks, reactors, driers, grinders, centrifuges and other pieces of equipment are readily used or adapted for a variety of products. With few exceptions such multiple usages is satisfactory provided the equipment can be adequately cleaned according to written procedures. Equipment that contains tarry or gummy residues that cannot be removed easily should be dedicated for use with these products only.

Some fermentation tanks, reaction vessels, and other equipment are not situated within a building and a considerable amount of processing occurs in a closed system.

Where temperature control is important, temperature recording devices should be used, with recording charts kept as part of the batch record.

4.2. Cleaning programme

Where multipurpose equipment is in use, it is important to be able to determine previous usage when investigating cross-contamination or the possibility of such contamination. An equipment cleaning and use log, while desirable and perhaps preferable, is not the only method of determining prior use. Any documentation system which clearly identifies the previous batch and shows that the equipment was cleaned is acceptable. For operations where multiple grades of the same chemical entity are processed, there must be documentation showing that the previous grade was removed. Validation data must exist to prove acceptability of the cleaning procedure.

Cleaning of multiple-use equipment should be confirmed. The manufacturer should determine the effectiveness of the cleaning procedures for each excipient or intermediate chemical used in that particular piece of equipment. The validation data required depend on the types of raw materials being made in the multiple-use equipment and the impact of trace contaminants on drug safety and performance. Validation data should verify that the cleaning process has removed residues to an acceptable level.

As an example, an equipment cleaning programme may include, but is not limited to, the following:

4.2.1. Detailed cleaning procedure

There should be a written equipment cleaning procedure that provides details of what should be done and which cleaning materials should be used. Some manufacturers list the specific solvents used for each excipient and intermediate.

4.2.2. Sampling plan

There should be some periodic testing after cleaning to ensure that the surface has been cleaned to the required level. One common method is to analyze the final rinse water or solvent for the presence of the substance last used in that piece of equipment. In some cases, visual inspections may be appropriate. A specific analytical method to determinate residual substances may not always be available, but is preferred. The need for an analytical method would be based on the potential adverse effect on product quality, performance or safety. When safety is a concern, there should be a specific analytical determination for a residual substance.

4.2.3. Analytical methods/cleaning limits

The toxicity of the residual materials should be considered when deciding on the appropriate analytical method and the residual cleaning limits. The residual limits established for each piece of apparatus should be practical, achievable and verifiable. The manufacturer should be able to show, with supporting data, that the residual level permitted is scientifically based. Another factor to consider is the possible non-uniformity of the residue. The level of residue found by random sampling, such as taking a swab from a limited area on a piece of equipment, does not necessarily represent the highest level of contamination.

5. Materials

5.1. General

In case of labile products that may be sensitive to environmental factors such as air, light, water, heat or cold, appropriate manufacturing and storage conditions must be used to ensure product quality throughout the process.

5.2. Starting materials

The excipient manufacturer should verify that the supplier of starting materials and components can meet the agreed-upon requirements. This may require periodic audits of the vendor’s plant if necessary. Purchasing agreements should contain data clearly describing the product ordered including, where applicable, the following:

- The name, type, class, style, grade, item code numbers or other precise identification as appropriate.

- Drawings, process requirements, inspection instructions and other relevant technical data, including requirements for approval or verification of product, procedures, process equipment and personnel.

Starting materials, including solvents and recovered solvents, are sometimes stored in silos or other large containers, making precise separation of batches difficult. Usage of such materials should be demonstrated, via inventory or other records, with reasonable accuracy.

When purchased and recovered solvents are commingled, the suitability of the recovered solvent must be demonstrated through either validation or actual testing. The purchased materials should comply with existing specifications.

Outdoor storage of starting materials (e.g. acids, other corrosive substances, explosive materials) is acceptable if the containers give suitable protection to their contents, identifying labels remain legible and containers are adequately cleaned prior to opening and use.

5.3. Rejected and recovered materials

Any starting material, intermediate or finished excipient not complying with specifications must be clearly identified and segregated to prevent inadvertent use or release for sale. A record of non-compliance should be maintained. All cases of non-compliance should be investigated to identify the root cause.

These materials may be:

- Reprocessed/reworked to meet the specified requirements;

- Regraded for alternative applications; or

- Rejected or scrapped.

Occasional reprocessing/reworking of an excipient may be acceptable. However, relying on the final testing only of the reprocessed excipient to demonstrate compliance to specification is not acceptable. The quality of the reprocessed material must be evaluated and documented showing adequate investigation and demonstrating that the reprocessed excipient is at least equivalent to other acceptable excipients. When reprocessing has to be done frequently, it may be an indication that the process, work instruction or training is inadequate and needs to be adjusted or reinforced.

5.4. Returned excipients

Returned excipients should be identified as such and kept. If the conditions under which the products have been stored and shipped or if the condition of the container itself casts doubt on the safety, quality or purity of the excipient, the product should be destroyed, unless thorough examination, testing, or other investigation shows that the product meets the appropriate predefined standards. If returned excipient containers are reused, all previous labelling should be removed or defaced. If the containers are used repeatedly solely for the same excipient, all previous batch numbers, or the entire label, should be removed or completely obliterated.

5.5. Storage practices

Pharmaceutical excipients should be stored under conditions established by the manufacturer on the basis of stability data. Records should be kept of the distribution of each batch of pharmaceutical excipient, to facilitate the recall of the batch if necessary, according to written procedures.

6. Documentation

6.1. General

The excipient manufacturer should have a system to cover all documents and data that relate to the requirements of the quality system. Documents, and subsequent changes to the documents, should be reviewed and approved by designated personnel before being issued to the appropriate areas identified in the documents. A record should be kept of where the documents are located.

The following minimal requirements for documentation should be applied:

- To assign a unique batch number to the excipient to be released and/or certified.

- To prepare a batch record.

- To demonstrate that the batch has been prepared under GMP conditions from the processing point at which excipient GMP have been applied.

- To demonstrate that the batch is homogeneous within the manufacturer’s specifications. This does not require a final blending of continuous process material, if process controls can demonstrate compliance with specifications throughout the batch.

- To demonstrate that the batch has not been commingled with material from other batches for the purpose of either hiding or diluting an adulterated substance.

- To demonstrate that the batch has been sampled in accordance with a sampling plan that ensures a representative sample of the batch is taken.

- To demonstrate that the batch has been analyzed using scientifically established tests and methods designed to ensure that the product meets accepted standards and specifications for quality, identity and purity.

- To demonstrate that the batch has stability data to support the intended period of use; these data can be obtained from actual studies on the specific excipient or from the applicable “model product” stability studies that can reasonably be expected to simulate the performance of the excipient.

6.2. Specifications

Starting material specifications should be organized to separate those tests that are routine from those that are performed infrequently or only for new suppliers. Relevant pharmacopoeial  monographs, when available, provide a basis for the development of internal manufacturer’s specifications.

A positive identification test uniquely applicable to the excipients should be established through analytical technology, such as infrared spectrophotometry and chromatography.

It is important that manufacturers identify and set appropriate limits for impurities. These limits should be based upon appropriate toxicological data, or limits described in national compendial requirements. Manufacturing processes should be adequately controlled so that the impurities do not exceed such established specifications.

Many excipients are extracted from or purified by the use of organic solvent. These solvents are normally removed by drying the moist excipient. In the view of the varying and sometimes unknown toxicity of solvents, it is important that excipient specifications include tests and limits for residues of solvents and other reactants.

Container specifications should be established for all excipients to assure consistency in protecting the product during transport from the excipient manufacturer to the pharmaceutical producer. The specifications should not only provide for containers that maintain the stability of the product, but should also meet requirements for protection during shipping, against insect infestation, during handling, etc.

6.3. Batch production records

Computer systems are increasingly used to initiate, monitor, adjust and otherwise control manufacturing processes. These operations may be accompanied by recording charts that show key parameters (e.g. temperature) at suitable intervals, or even continuously, throughout the process. In other cases, key measurements (e.g. pH) may be displayed temporarily on a monitor screen, but are not available in hard copy.

Records showing addition of ingredients, actual performance of operations by identifiable individuals, and other information usually seen in conventional records, may be missing. When computers and other sophisticated equipment are employed, the emphasis must be change from conventional, hand-written records to:

- Systems and procedures that show the equipment and software are in fact performing as intended;

- Checking and calibration of the equipment at appropriate intervals;

- Retention of suitable back-up systems such as copies of the program and files, duplicate tapes or microfilm;

- Assurance that changes in the program are made only by authorized personnel and that they are clearly documented and validated.

6.4. Other documents

Shipping and storage requirements should be established to ensure that the product reaches the manufacturer with proper quality attributes. This should be mutually agreed upon between the vendor and purchaser and established prior to transportation of product.

Written procedures should be established and followed for maintenance of equipment. All maintenance activities performed must be recorded. This may be in the form of a log, computer database or other appropriate documentation, as long as the system can identify who was responsible for performing each function.

7. Good practices in production and quality control

7.1. Change control and process validation

Process changes may lead to changes in inherent product characteristics. Manufacturers should have a formal process change system in place, with written standard operating procedures covering such changes. Management of the change system should be assigned to an independent quality unit having responsibility and authority for final approval of process changes.

Excipient manufacturers often produce laboratory or pilot batches. Scale-up to commercial production may involve several stages and data should be reviewed to demonstrate the adequacy of the scale-up process. Scale-up may introduce significant problems of consistency between patches. Pilot batches should serve as the basis for establishing in-process and finished product purity specifications.

Manufacturers will generate reports that discuss the development and limitation of the manufacturing process. Summaries of such reports should be reviewed to determine if the plant is capable of producing the excipient. The report serves as the basis for the validation of the manufacturing and control procedures, as well as the basis documentation to demonstrate that the process works consistently.

A document comprising scale-up data and describing the process reactions, operating parameters, purifications, impurities and key tests needed for process control should be written. A retrospective analysis of historical data (through statistical data and process capability data analysis) as well as the previous documentation will provide a good basis for validation.

7.2. Good practices in production

7.2.1. Prevention of cross-contamination

Potential for cross-contamination should be considered in the design of the manufacturing process and facility. The degree to which cross-contamination should be minimized depends on the safety and intended use of the excipient.

The precautions taken to minimize cross-contamination should be appropriate to the conditions of the manufacturing facility and will take account of the range of materials manufactured. When the excipient product is initially recovered, it should be in a clean environment and not exposed to airborne contaminants, such as dust from other excipient or industrial chemicals. Typically, the damp product will be unloaded into clean, covered containers and transported for drying and other manipulations. These subsequent operations should be performed in separate areas or under controlled conditions because once dry, the excipient is more likely to contaminate its environment, including any surrounding products. The primary consideration is that the building and facilities should not contribute to an actual or potential contamination of the excipient.

The air handling systems at the site of manufacture should be designed to prevent cross-contamination. In dedicated areas processing the same excipient, it is permissible to recycle a portion of the exhaust air back into the same area. The adequacy of such a system of operation for multi-use areas, especially if several products are processed simultaneously, should be carefully analyzed. in multi-use areas where several products are completely confined in closed vessels and piping systems, filtration of the supply air (combined fresh make-up air and recycled air) is acceptable if the conditions are consistent with other existing regulations (e.g. environmental, safety).

In those areas where the excipient is in a damp or moistened form, such as filter or centrifuge cake, and may be exposed to room air, filter efficiencies in the supply air system as low as 85% may be adequate. In those areas where one or more of the products is being processed in a dry form, such filtration may not be enough to prevent cross-contamination. In all cases, manufacturers should be able to demonstrate the adequacy of their air handling systems.

Excipient manufacturers should have a documented programme identifying all insecticides, pesticides, rodenticides and herbicides used at the site manufacture. Adequate measures should be taken to prevent these agents contaminating the excipients.

7.2.2. In-process blending/mixing

Some processes require blending or mixing. Such in-process blending is acceptable provided it is adequately documented in batch production records. Examples include:

- Collection of multiple batches or continuous accumulation of batches with defined endpoint in a single holding tank (with a new batch number).

- Recycling material from one batch for further use in a subsequent batch.

- Repeated crystallizations of the same mother liquor for better yield of crystals.

- Collecting several centrifuge loads in a single drier/blender.

Incidental carry-over is another type of in-process mixing that frequently occurs. Examples include:

- Residue adhering to the wall of micronizer used for milling the finished excipient.

- Residual layer of damp crystals remaining in a centrifuge bowl after discharge of the bulk of the crystals from a prior batch.

- Incomplete discharge of fluids, crystals or particles from a processing vessel upon transfer of the material to the next step in the process.

These residues are usually acceptable since clean-up between successive batches of the same excipient is not normally required during production. However, in the case of non-dedicated production units, complete cleaning procedures designed to prevent contamination that would alter the quality of the substance must be employed when changing from one excipient to another. Checking the effectiveness of these cleaning procedures may require the use of analytical testing for the substances involved.

In contract to in-process blending and incidental carry-over discussed above, other blending operations should be directed towards achieving homogeneity of the finished excipient batch. Three areas in the processing of finished batches of an excipient which should be examined carefully and critically are:

- The final blending operation to produce the finished batch;

- The point in the process at which the batch number is assigned;

- The sampling procedure used to obtain the sample that is intended to be representative of the batch.

Blending of excipient batches to salvage adulterated material is not an acceptable practice.

Mother liquors containing recoverable amounts of excipients are frequently reused. Secondary recovery procedures for such excipients are acceptable, if the recovered excipient meets it specifications and if recovery procedures are indicated in batch production records. Secondary recovery procedures for reactants and intermediates are acceptable provided that the recovered materials meet suitable specifications.

7.2.3. Control of microbial contamination

The manufacture of sterile excipients for use in aseptic/sterile processing presents technical challenges. It is essential that adequately qualified and trained personnel be used to supervise and perform procedures associated with the manufacture of sterile excipients. The environment in which procedures are conducted, and the operators themselves, are significant potential source of contamination in aseptic operations. Processes should be designed to minimize contact between excipient and the environment and the operators. Those aseptic excipient operations which require considerable operator involvement must have adequate controls. Major potential problem areas include aseptic removal of the excipient from centrifuges, manual transfer to drying trays and mills, and the inability to sterilize the drier. Not all equipment currently in use can be sterilized.

The excipient manufacturer must document the cleaning of critical processing equipment such as centrifuges and driers. Any manipulation of sterile excipients after sterilization must be performed as a validated aseptic process. This is particularly important for those excipients which are not further sterilized prior to packaging into final containers. In some instances, the compendial monographs may specify that an excipient which does not meet parenteral grade standards must be labelled as not suitable for use in the preparation of injectable products.

Some manufacturers of non-sterile excipients use heat, gamma radiation and other methods to reduce the microbial burden. These methods are acceptable provided the manufacturer has shown that the product meets microbial requirements and that the process is under control within the manufacturer’s specifications. Any procedure should be validated in accordance with recognized international standards to demonstrate that the process will produce the intended result. Post-production treatment of excipients should not be used as a substitute for attention to microbiological control during production.

A protected environment may be necessary to avoid microbial contamination or degradation caused by exposure to heat, air or light. The degree of protection required may vary depending on the stage of the process. Often, direct operator contact is involved in the unloading of centrifuge bags, transfer hoses (particularly those used to transfer powders), drying equipment and pumps, and equipment should be designed to minimize the possibility of contamination. The sanitary design of transfer and processing equipment should be evaluated. Those with moving parts should be assessed for the integrity of seals and other packing materials to avoid product contamination.

Special environments required by some processes must be monitored at all times to ensure product quality (e.g. inert atmosphere, protection from light). If interruptions in the special environment occur, adequate evidence must be provided that they have not compromised the quality of the excipient. Such environmental concerns become increasingly important after purification of the excipient has been completed.

The environment to which the excipient may be exposed should be similar to that used in the manufacture of the final dosage form. This is especially true in the case of excipients intended for parenteral dosage forms. For example, controlled areas may need to be established along with appropriate air quality classifications. Such areas should be serviced by suitable air handling systems and there should be adequate environmental monitoring programmes. Any manipulation of sterile excipient after sterilization must be performed as an aseptic process, using Class 100 air and other aseptic controls.

7.2.4. Water systems/water quality

While drinking water is used for many excipient processes, purified water is also widely used. Because of the well-known potential for microbial growth in deionizers and ultrafiltration or reserve osmosis systems used to produce purified water, such systems must be properly validated and checked. Proper control methods include the establishment of water quality specifications and corresponding action levels, remedial action when microbial levels are exceeded and adequate maintenance procedures such as regeneration and sanitation/sterilization.

Appropriate specifications for chemical and microbial quality should be established and periodic testing conducted. Such specifications will vary depending on the process and the point in the process when the water is used. For example, in some cases, if the water is used in later processing steps such as for a final wash of the filter cake, or if the excipient is crystallized from an aqueous system, the water quality standards may need to be higher than normally specified or purified water. This is particularly important where the excipient’s intended use is in parenteral dosage forms. The frequency of microbial and chemical testing of purified water depends on a variety of factors, including the test results and the point in the process (e.g. final wash in centrifuge) at which such water is used.

Most purified water and water for injection systems, including reverse osmosis and ultrafiltration systems, have the potential for endotoxin contamination. If the final excipient is supposed to be pyrogen free or sterile, or will be used in preparing parenteral products, validation of the system to control endotoxins should be conducted and routine testing of the process water for endotoxins should be performed (preferably by the LAL (Limulus amoebocyte lysate) method).

7.2.5. Packaging operations

When the programme for packaging operations is being set up, particular attention should be given to minimizing the risk of cross-contamination, mix-ups, or substitutions. Different products should not be packaged in close proximity unless there is physical segregation or the use of electronic surveillance.

7.2.6. Delivery

The manufacturer should arrange for the protection of the product after final inspection and testing. Where contractually agreed, this protection should include delivery to destination. Distribution records should be kept.

7.3. Good practices in quality control

7.3.1. General

The quality control unit, in addition to having the responsibility and authority to approve or reject all components, in-process materials, packaging materials and finished excipients, and to review production records, etc., should also be responsible for approving or rejecting excipients manufactured, processed, packaged, or held under contract by another company, as well as for approving or rejecting all procedures, specifications and process changes having an effect on the quality of the excipient.

7.3.2. Control of starting materials

All starting materials must be tested or otherwise verified prior to use. Verification should include a certificate of analysis from the supplier and, wherever feasible, an identification test. There should be clear guidance or standard operating procedures established for the approval of each starting material.

Starting materials are usually subjected to an identity test and additional testing to confirm that they meet appropriate specifications. Some starting materials may not be acceptance tested by the manufacturer because of the hazards involved or other valid considerations. In such cases, quality certification for each batch from the vendor should be on file. There should always be some evidence of an attempt by the excipient manufacturer to establish identity, even if it is only a visual examination of containers, examination of labels, or recording of batch numbers from the labels.

7.3.3. In-process testing

In-process inspection and testing should be performed by monitoring the process or by actual sample analysis at defined locations and times. The result should conform to established process parameters or acceptable tolerances. Work instructions should delineate the procedure to follow and how to use the inspection and test data to control the process.

7.3.4. Quality records and retention samples

The manufacturer should establish and maintain procedures for identification, collection, indexing, filing, storage, maintenance and availability of quality records. Quality records should be maintained to demonstrate achievement of the required quality and the effective operation of the quality system. These data should include pertinent subcontractor quality records.

All quality records should be legible and identifiable to the product involved. Quality records should be stored and maintained in such a way that they are readily retrievable, in facilities that provide a suitable environment to minimize deterioration or damage and to prevent loss. Retention times of quality records should be established and recorded. Where agreed contractually, quality records should be made available for evaluation by the purchaser or the purchaser’s representative for an agreed period.

All appropriate records relating to inspection and testing must be available for review. Where the process is continuously monitored, acknowledgement must be made of this and the result of the monitoring should be available.

Reserve samples of the released excipient should be retained for 1 year after the expiry or re-evaluation date, or for one year after distribution is complete. Sample size should be twice the amount required to perform release specification testing.

7.3.5. Stability studies

Many excipient products are very stable and may not require extensive testing to check stability. The stability of some excipients may be affected by undetected changes in starting material specifications, or subtle changes in manufacturing procedures. Excipients may also be shipped in a large variety of different packaging types that can affect their stability (e.g. metal and plastic drums, bags, plastic and glass bottles, bulk tanks).

Some excipients may be similar in chemical structure to other excipients, and some may be mixtures or blends of other excipients. These excipients may be very similar to others within a product group. Minor quantitative differences of some of the components may be the only significant variation from one product to another. For these excipients, a “model product” approach to assess the stability may be appropriate. Stability studies of this type should involve selection of several “model products” that would be expected to simulate the stability of the product group being assessed. This selection must be scientifically based. Data from stability studies of these “model products” can be used to determine the theoretical stability of similar products.

The full stability testing programme, when needed, usually contains the following features and takes into account historical data:

- The programme should be formalized in writing and ongoing studies should be reviewed at least annually.

- The programme should periodically include a sample from at least one commercial size batch.

- Stability samples should be stored in containers that approximate the primary market container. Simulations of all types of containers are not required, unless there are theoretical reasons to indicate that stability may be affected by container type.

- The samples should be stored under conditions similar to those recommended for the marketed excipient product.

- Additional samples may be stored under stress conditions (e.g. elevated temperature, light, humidity or freezing) if such conditions might reasonably be encountered during distribution and storage.

- Stability-indicating test methods should be used.

- Where stability of the excipient appears to be a significant issue is its use in pharmaceutical manufacturing, additional periodic testing of either the specific material or “model products” may have to be performed to ensure that the expected stability does not significantly change with the future batches. The frequency of testing should be determined by the impact that the excipient’s stability may have on its usage

7.3.6. Expiry/re-evaluation dating

Conducting a stability testing programme does not necessarily mean that expiry dates must be used. Where stability testing indicates a limited shelf-life, the label should declare an expiry date of indicate the need for re-evaluation testing at an appropriate interval to assure quality at time of use. If the need for special storage conditions exists (e.g. protection from light, heat) such restrictions should be placed on the label.

7.3.7. Calibration of measuring and test equipment

All measuring and test equipment identified as being part of the quality system should be properly calibrated and maintained. This includes all in-process instruments identified as critical quality instruments, as well as test equipment used in the laboratory. The control programme should include the standardization or calibration of reagents, instruments, apparatus, gauges and recording devices at suitable intervals, in accordance with an established written programme containing specific directions, schedules, limits for accuracy and precisions, and provisions for remedial action in the event that accuracy and/or precision limits are not met. reagents, instruments, apparatus, gauges and recording devices not meeting established specifications should not be used. Computer systems used to verify that the product conforms to specifications must be audited to ensure satisfactory performance in the laboratory.

APPENDIX 4

(Promulgated together with Circular No. 29/2020/TT-BYT dated 31/12/2020 of the Minister of Health)

REPORT (1)

Violations committed by bidders during bidding and supply of drugs

To: ..........................................................................

Pursuant to Clause 4 Article 5 of Circular No. 15/2019/TT-BYT, .... <name of reporting unit> .... prepares a report on Violations committed by bidders during bidding and supply of drugs in the year: