Lecture 1 Role of Pharmaceutical Inspector in regulating medicinal products

Question 1

What are some things that can be falsified for medicinal products/APIs?

Answer 1

1. Name of Manufacturer
2. Name of Market Authorization Holder
3. Batch Number
4. Packaging/Labeling
5. Identity/Composition
6. Manufacturing Records/Certificates of Analysis

Question 2

Who can make contaminated medicinal products?

Answer 2

• Licensed Manufacturers (unwittingly) when producing multiple products using multi-purpose equipment in facilities lacking cross-contamination control program
• Backyard Manufacturers

Question 3

Is it possible to judge the quality of a medicinal product by its appearance or presentation?

Answer 3

No

Question 4

What do consumers trust the regulators to do?

Answer 4

• to weed out adulterated, counterfeits and falsified products
• to ensure safe, efficacious and quality products
• to oversee drug/API manufacturing and supply chain

Question 5

Under Singapore Medicines Act/Health Products Act, what is required for manufacture of medicinal products (therapeutic products)?

Answer 5

Manufacturer’s Licence

- Compliance with PIC/S GMP standard is pre-requisite for issuance and retention of Manufacturer’s Licence

Question 6

How often are GMP compliance audits conducted?

Answer 6

Periodic audits (18-36 months frequency)

Question 7

When did Singapore join the PICS?

Answer 7

1 Jan 2000 as the 1st Asian Member

Question 8

What is PICS?

Answer 8

Pharmaceutical Inspection Co-operation Scheme

- based in geneva consisting of countries with high standard inspection systems

Question 9

What is the latest version of PICS guide?

Answer 9

Version 14 dated July 2018

Question 10

What is GMP?

Answer 10

Good Manufacturing Practices

Question 11

Purpose of GMP?

Answer 11

Ensure a medicinal product is consistently manufactured and controlled, its quality is appropriate for use as per market authorization (product license)

Question 12

How many chapters are there for the PICS GMP standard?

Answer 12

9

Question 13

What is the goal of PICS?

Answer 13

“To lead the international development, implementation and maintenance of Harmonised GMP Standard (for Manufacturers) and Quality System (for Inspectorates) in the field of medicinal products”

Question 14

What do the PICS chapters comprise of?

Answer 14

1. Pharmaceutical Quality System (including Product Quality Review and Quality Risk
2. Personnel
3. Premises and Equipment
4. Documentation
5. Production (including Packaging)
6. Quality Control
7. Outsourced Activities (Contract Manufacture and Analysis)
8. Complaints and Product Recall
9. Self inspection (IQA)

Question 15

Where do we inspect the starting materials? (APIs, Excipients and Packaging Materials)

Answer 15

Warehouse

Question 16

What is the flow of on-site inspection?

Answer 16

1. Warehouse
2. Weighing room/Production areas/Packaging Room
3. QC labs
4. Document audit

Question 17

What are the 3 objectives of warehouse inspection?

Answer 17

1. Starting materials and finished products are approved
2. SOPs in place
3. Environment of warehouse

Question 18

What is/are the relevant PICS GMP chapter(s) for warehouse inspection?

Answer 18

• Chapter 3 (Premises : Storage Areas)

- Chapter 5 (Production : Starting Materials)

Question 19

What are the objectives of weighing room inspection?

Answer 19

1. Calibrated, Accurate and Reliable weighing balances used
2. Weighed materials are of correct identity, quantity and quality
3. Environment and authorized personnel in PPE to prevent cross contamination

Question 20

What is/are the relevant PICS GMP chapter(s) for weighing room inspection?

Answer 20

Chapter 5 (Production : Dispensing)

Question 21

What are the 5 objectives of Production room inspection?

Answer 21

1. Premises designed for prevention of cross-contamination
2. Effective cleaning of equipment and regular maintenance
3. Personnel control programs (PPE and restricted access)
4. Materials of correct identity, quantity and quality
5. Process Controls (Validation/revalidation, In-process QC, batch processing records in place)

Question 22

What is/are the relevant PICS GMP chapter(s) for production room inspection?

Answer 22

Chapter 5 (Production : Paragraphs 5.1 to 5.71)

Question 23

What are the Items/Areas Covered during Inspection of Production Department?

Answer 23

PMMMM

• Production rooms (Premises)
• Production equipment (Machine)
• Production process (Method and starting Materials)
• Personnel (Manpower)

Question 24

What are the objectives of QC department inspection?

Answer 24

1. Properly trained analysts available with independent authority for head of QC
2. Approved QC methods with Analytical Method Validation and Routine QC Test Results
3. SOPs are in place (Maintenance, Calibration, Status Labeling and Assuring Integrity of QC Test Equipment, Receipt, Storage, Security, Record keeping of Test Samples, Reagents and Reference Standards)

Question 25

What is covered under inspection of the chemistry testing laboratory?

Answer 25

- Test samples - Prepared Reagents - Reference standards (chemical) - Retention Samples (for stability or regulatory testing) - Test Methods - Failure Investigation (Out-of-Specification - OOS) - Stability Studies

Question 26

What are some of the other areas/activities inspected?

Answer 26

- Ancillary premises (Engineering workshop, Rest room and corridors) - External Premises/outsourced activities (contract testing laboratories)

Question 27

What are the 4 objectives of Document audit?

Answer 27

1. Legal requirements under Medicines and Health products act are complied 2. Regulatory Commitments to HSA are Complied by Manufacturer 3. Manufacturing SOPs, including those on Product Quality Reviews, Handling of Complaints and Recalls and Self Inspection, are followed 4. Manufacturing Records are Authentic No Falsification of Data

Question 28

What are the areas covered under documentation audit?

Answer 28

- Document control system - SOP and Records on Pest Control, Temperature/ humidity monitoring - Batch Manufacturing records - Stability testing program - Process validation program - GMP training program - SOP and Records on Product quality review - SOP and Records of Product complaints and Recalls - SOP and Records of Self-Inspection (IQA) program

Question 29

How should Product Quality Review (PQR) results be used?

Answer 29

PQR results trended , investigated with CAPAs taken based on Root Cause Analysis

Question 30

How should the complaint department be set up?

Answer 30

- Designated person to handle complaints and decide on actions to take - Written SOP on handling complaints - All complaints are recorded, investigated and closed out with decisions taken documented - All complaint records should be reviewed regularly for any recurring trend - HSA to be notified if a product recall is made by the manufacturer

Question 31

Who should manufacturer notify if they are considering a product recall?

Answer 31

- The Competent Authority (Regulatory Authority) should be notified, for all the countries the product is sold in

Question 32

Who should coordinate and execute product recalls?

Answer 32

A designated person , independent of Sales and Marketing, should be responsible for coordinating and executing recalls

Question 33

What are the documents needed in a product recall?

Answer 33

1. Written SOP 2. Distribution Records 3. Progress of recall process should be recorded and final report issued, including a reconciliation between delivered and recovered products

Question 34

What is done with the recalled product?

Answer 34

Recalled product should be stored securely while awaiting decision on its fate

Question 35

What should be done with the recall procedure?

Answer 35

Effectiveness of recall procedure should be evaluated regularly

Question 36

What are the areas covered during self-inspection?

Answer 36

The areas covered during self inspection should include production, QC, premises, equipment, personnel, documentation, etc (i.e. all 9 chapters and relevant annexes of PICS GMP standard)

Question 37

Who should conduct self-inspections?

Answer 37

- Self inspection should be conducted in an independent and detailed way by designated competent persons from company - Independent audits by external experts are also useful

Question 38

What are the documentation necessary for self-inspections?

Answer 38

- All self inspections should be recorded , covering observations made during inspections and proposed CAPAs - Statement(s) of eventual action(s) taken should also be recorded

Question 39

How often should self-inspections be conducted?

Answer 39

Self Inspections should be carried out at periodic intervals in accordance with pre arranged program

Question 40

Which of the chapters/annexes of the PICS GMP standard are mandatory?

Answer 40

The 9 chapters are mandatory but not all annexes are mandatory (i.e. 4, 5, 16, 20 in SG) annex 4: manufacture of non-immunological veterinary pdts annex 5: manufacture of immunological veterinary pdts annex 16: qualified person and batch release annex 20: quality risk management

Question 41

Which annexes are not implemented in SG?

Answer 41

Annex 4 - Manufacture of (Non Immunological ) Veterinary Products Annex 5 - Manufacture of (Immunological) Veterinary Products Annex 16 - Qualified Person (QP) and Batch Release : Applicable to EU Only Annex 20 - Quality Risk Management : Voluntary