L1 Flashcards
Slim10
adulterated chinese proprietary medicine
- appears good, sleak and elegant: health risks not obvious
- adulterated with nitro-enfluramine, caused deaths and liver toxicity in many patients (2003, SG and Asia)
Adulterated products
Slim10 (CPM), heparin injection (medicinal product)
Heparin injections
adulterated medicinal product, by baxter healthcare
- adulteration occured at uninspected premises
- appears good, health risks not obvious
- adulterated with oversulphated chondroitin sulphate (OSCS), mimics chemistry and pharmacology of heparin
- caused more than 100 deaths and hundreds of serious allergic reactions
- 2008, US and 10 other countries
Counterfeit medicinal product
appears good and IDENTICAL, health risks not obvious
- serious quality, health risks and patient violation issues
- often made by backyard manufacturers
- authentic lot: A052788
- counterfeit lot: A041410
What is the difference between manufacturers of counterfeit medicinal products and contaminated medicinal products?
Contaminated medicinal products are made by licensed manufacturers
- a problem with manufacturers producing multiple products using multi-purpose equipment in facilities lacking cross-contamination control program
Falsified medicines
medicinal products/API with false representation
What are the types of information that may be falsified? (6)
- name of manufacturer
- name of market authorisation holder
- batch number
- packaging/labelling
- identity/composiition
- manufacturing records/certificates of analysis
Regulators (inspectors, reviewers and analysts)
- weed out adulterated, counterfeits and contaminated products
- ensure safe, efficacious and quality products
- oversee drug/API manufacturing and supply chain
What is the pre-requisite for issuance and retention of manufacturer’s license?
Compliance with PIC/S GMP standard
- GMP compliance assessed through 18-36 months periodic audits by inspectors from HSA
Role of pharmaceutical inspector
Inspecting manufacturer’s compliance to PICS GMP standard
How many members are there in PIC/S, as of 1st Jan 2020?
53
When did Singapore join PIC/S?
1 jan 2000, first asian member
What is PIC/S goal?
lead the international development, implementation and maintenance of harmonised GMP standard (for manufacturers) and quality system(for inspectors) in the field of medicinal products
- include herbal, API, biological, clinical trial products
Where was PIC/S based in?
Switzerland
When was the latest PIC/S GMP standard revision?
2018
- dynamic, undergoes revision from time to time
When was HSA formed?
April 2001
What is GMP?
A quality system standard implemented by pharmaceutical manufacturers to help ensure that:
- a medicinal product is consistently manufactured and controlled
- to the quality appropriate for its intended use(s), and
- as required by its market authorisation (aka product license)
How many chapters are there in the PIC/S GMP standard? And what are they?
- pharmaceutical quality system
- personnel
- premises and equipment
- documentation
- production, including packaging
- quality control
- outsourced activities (contract manufacture and analysis)
- complaints and product recall
- self-inspection (IQA)
Conventional manufacturing flow (places)
- warehouse
- weighing room, production areas, packaging
- QC laboratories: chemistry lab, microbiology lab
- document audit: SOP, records, reports, etc
Which chapters in the PICS guide refer to ‘warehouse’?
chapter 3 (premises: storage areas), chapter 5 (production: starting materials)
Objective of warehouse inspection
assess that:
- all starting materials ie. APIs, packaging materials and finished products have approved specifications and materials are purchased from approved suppliers
- procedures (SOP) are in place for handling receipt, quarantine, sampling (including availability of sampling room), release of materials and for handling rejected materials and products
- environment of warehouse eg temp and RH monitoring and pest control programs, preserves quality of materials and products stored
Objective of weighing room inspection
- calibrated, accurate and reliable weighing balances are used
- weighed materials are of correct identity, quantity and quality
- authorised personnel wear appropriate PPE and environment of weighing room controlled to prevent cross contamination
Which chapters in the PICS guide refer to ‘weighing room’?
Chapter 5 (production: dispensing)
What are the items covered during audit of weighing room?
- calibration of weighing balances
- labelling of starting materials
- personnel wear proper gowns and ppe
- SOP for weighing method (and records of weighing)
- dust extraction system and housekeeping of weighing room
Which chapters in the PICS guide refer to ‘production department’?
Chapter 5 (production: paragraphs 5.1 to 5.71)
objectives of inspecting production department
assess that:
- premises are designed to prevent corss-contamination
- equipment are effectively cleaned and regularly maintained
- personnel control programs are in place: restricted access only to authorised personnel, authorised personnel wear appropriate gowns and ppe
- materials of correct identity, quantity and quality are used for production
- process controls are in place eg. critical processes are validated/re-validated, in-process quality controls are in place, comprehensive batch processing records are kept
items/areas covered during inspection of production department
Production Rooms (premises), equipment (machine), process (method), personnel (manpower)
inspection of production department: premises
- design/construction
- partition/segregation, air-handling and containment
- connecting pipe-work (stainless steel) and drainage (no back flow)
- change room (appropriate class and air shower)
- cleaning/maintenance and records
- environmental and micrbiological monitoring
inspection of production department: machine
- design and construction
- cleaning/maintenance, calibration and usage records
- status labelling of equipment
inspection of production department: method
- labelling/control of weighed starting materials
- gowning of production personnel
- batch production records
- process deviation and investigation
- process validaiton, revalidation and change controls
inspection of production department: manpower
- wear appropriate ppe and do not wear cosmetics/jewelry
inspection of packaging room: premises
- design and construction
- cleaning/maintenance and calibration
- environmental and microbiological monitoring
inspection of packaging room: machine
- cleaning/maintenance, calibration and usage records
- status labeling of equipment
inspection of packaging room: method
- control of labels and packaging materials, bulk and finished products
- batch packaging records
- validation/revalidation and change controls
inspection of packaging room: manpower
- gowns and ppe of operators
Which chapters in the PICS guide refer to ‘QC department’?
chapter 6 (quality control: paragraphs 6.1 to 6.41)
objectives of inspecting qc department/labs
assess that:
- properly trained analysts are available and there is independent authority for head of qc
- qc test methods are approved by HSA and are robust, sensitive, accurate and reliable for testing as evident from records of analytical method validation and routine qc test results
- procedures are in place for maintenance, calibration, status labeling and assuring integrity of qc test equipment, eg. hplc, gc, dissolution tester
- procedures are in place for receipt, storage, security, record-keeping of test samples, reagents and reference standards
areas/items covered under inspection of qc laboratories
chemistry testing laboratory
- test samples (api, finished products, water, swabs, etc)
- prepared reagents
- reference standards (chemical): pri, sec
- retention samples (for stability or regulatory testing)
- test methods: types (eg ID, assay, DT), calibration of equipment, validation, raw data records and print-outs
- failure (OOS) investigation
- stability studies
objectives of documentation audit (SOPs, records, reports, etc)
assess that:
- legal requirements under medicines and hpa are complied by manufacturer
- regulatory commitments to HSA are complied by manufacturer: eg. composition of finished products and specifications of starting materials, test methods used, process valisation/stabiltiy study reports-protocols and acceptance criteria
- manufacturing SOPs, incl those on product quality reviews, handling of complaints and recalls and self-inspection, are followed
- manufacturing records are authentic: no falsification of data
manufacturer conforms to legal and regulatory requirements and PIC/S GMP standard
PQR
chapter 1: PQR should be conducted annnually on all authorised products:
- quality of starting materials
- quality of finished products and critical in-process controls
- failed batches of products
- manufacturing process/qc deviations
- changes to manufacturing processes and analysis methods
- changes to market authorisations (product licenses)
- stability testing program
- complaints and product recalls: investigations and closed out
- adequacy of previous CAPAs carried out
- qualification status of key equipment and utilities ef water, HVAC, steam
complaints
chapter 8
- a designated person should be responsible for handling complaints and deciding on actions to be taken
- a written procedure (SOP) on handling complaints should be in place
- all complaints shall be recorded, investigated and closed out with decisions taken documented
- all complaint records should be reviewed regularly for any recurring trend
- the Competent Authority (Regulatory Authority) should be notified if manufacturer is considering product recall following serious quality defects, faulty manufacture and evidence of counterfeit products
recalls
chapter 8
- a designated person, independent of Sales and Marketing, should be responsible for coordinating and executing recalls
- a written procedure (SOP) should be in place for product recalls
- distribution reocords should be readily available to the designated person
- the Competent Authorities (Regulatory Authorities) where the product is distributed, should be notified if manufacturer is considering product recall
- recalled product should be stored securely while awaiting decision on its fate
- progress of recall process should be recorded and final report issued, including a reconciliation between delivered and recovered products
- effectiveness of recall procedure should be evaluated regularly
self-inspection
chapter 9
- should be carried out at periodic intervals in accordance with pre-arranged program
- areas covered during self-inspection should include production, QC, premises, equipment, personnel, documentation, etc. (all 9 chapters and relevant annexes of PICS GMP standard)
- conducted in an independent and detailed way by designated competent persons from company
- independent audits by external experts are also useful
- should be recorded, covering observations made during inspections and proposed CAPAs
- statement(s) of eventual action(s) taken should also be recorded
Are all annexes mandatory?
No!
What are the annexes for?
stipulates additional requirements for various types of medicinal products and gmp-related matter
PICS GMP standard - 20 annexes
- manufacture of sterile products: sterilisation and clean rooms
- manufacture of biological products: proteins susceptible to heat and low pH
- manufacture of radiopharmaceuticals: short shelf lives
- manufacture of (non-immunological) veterinary products - not regulated in sg
- manufacture of (immunological) veterinary products - not regulated in sg
- manufacture of medicinal gases eg. nitrous oxide for anaesthesia
- manufacture of herbal medicinal products: prone to microbial growth
- sampling of starting and packaging materials
- manufacture of liquids, creams and ointments
- manufacture of inhalations
- computerised systems: electronic records and data integrity awareness (GDocP and data integrity)
- use of ionising radiation in manufacturing
- manufacture of investigational medicinal products (clinical trial pdts)
- manufacture of blood products: screening of plasma/blood donors
- qualification and process validation: assuming product homogenity
- qualified person (QP) and batch release: applicable to EU only - not applicable in SG
- parametric release (batch release based on critical parameters)
- empty (previously GMP standard for APIs - renamed PICS guide to GMP part 2)
- reference and retention samples: ongoing stability testing and disputes
- quality risk management: voluntary
