1. April 12, 09 A. Saffari, PH.D Former WHO Technical Officer
GMP & VALIDATION
April 12, 09
A. Saffari, PH.D
Former
WHO Technical Officer

2. Training content Quality of medicines What is GMP
Regulation in Pharma industry
The Food and Drug Administration
European Regulations
Validation/ Qualification

3. Why medicines are special category of products?
Because consumers, patients and health care workers have limited or no capacity to judge the three critical factors in medicines they use
Safety
Quality
Efficacy

4. A Modern Fable About Quality

5. Quality of Medicines
Quality of medicine CAN NOT BE seen nor can be detected by
usual perception even for professional workers; pharmacist and doctors
Taste
Appearance
Smell

6. Are all medicines safe, effective and meet quality criteria?
No, they are not, and No, they do not !
Some are safe, but not effective
Some may be effective and do meet quality criteria but are not safe
Some meet quality criteria but are not necessarily safe nor have any efficacy

7. GMP for Human and veterinary products
Volume 4, EU Guideline to GMP, Medicinal products for Human and Veterinary use
All member states and the industry agreed that the GMP requirements applicable to the manufacturer of veterinary medicinal products are the same as those applicable to the manufacturer of medicinal products for human use

8. What is GMP?
A sets of regulations aim at ensuring products are consistently produced and controlled to the quality standards appropriate for their intended use
GMP is the CULTURE that should and must be integrated into product
GMP It is designed to minimize risks involved in production of human production
Quality of product is determined by the state of GMP COMPLAINCE

9. How GMP Came About? Defined by Health Authorities
The result of historic evolution– many bad experince
Has been changed through times:
Becomes wiser
Mistake and fraught has been discovered (--. Pre-approval)
Is still changing:
cGMP: Current Good Manufacturing Practice

10. History of GMP Evolution
1962 Food and Drug Administration (FDA)
1969 WHO
1971 FDA GMP Guidelines
1978 FDA cGMP
1987 EC GMP Guide
PICS (pharmaceutical inspection convention scheme)
ISPE (international standards for pharmaceutical Engineering

11. GMP Content Basic, Quality management Sanitation
Qualification & validation
Premise & Equipment
Documentation
QC,
Manufacturing
Complaints and Recall
Self inspection
Personnel
Materials

12. Content of GMP Advance Validation Water
Heating Ventilation & Air Conditioning (HVAC)
Sterile production

13. What do we get by GMP compliance
Better economy
Less rejects
Faster product release
Less complaints
Better image
Authorities
Less risk for audit observations
Less risk for market withdrawals
Less risk for revoke of market – or manufacturing authorizations
Better quality
Increased product safety
Less undetected errors

14. Basic GMP requirements
All manufacturing processes must be clearly defined, systematically reviewed and proven to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications
Critical steps of manufacturing processes and significant changes to the process must be validated
Instructions and procedures must be written
Operators must be trained to carry out procedures correctly
Records made during manufacture must demonstrate that all steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected.
Deviations are fully recorded and investigated
A system must be in place to recall any batch of product, from sale or supply
Complaints about marketed products must be recorded and investigated measures must be taken to prevent reoccurrence.

15. Quality Management System (QMS)QC QA
GMP
Quality Management System manages all activities
that can influence quality of product

16. Personnel Requirements
Job description
Qualification
Training
Hygiene programms

17. Equipment & Premise Design Capacity Conditions Qualification
Maintenance
Calibration

18. Why GMP (great mountains of Papers)?
Documentation is the KEY issue in GMP
If you have not documented what you did, then you did not do it all

19. Documentation Essential part of Quality Assurance
Defines specifications and procedures for all materials and methods of manufacture and control
Ensures all personnel know what to do and when to do
Ensure that authorized persons have all information necessary for release of product
Ensures documented evidence, traceability, records and audit trail for investigation are available
Ensures availability of data for validation, review and statistical analysis

20. Why documents are so important?
Traceability
Prove of action
If it is not documented, it did not happened
Communication
Consistency
Requirements for regulatory inspection
A Key to inspection

21. Production Written procedures In-process quality control Labelling
Validation
Prevention of cross-contamination
Starting materials (approved suppliers, verification, release, dispensing)
Processing operations (line clearance, deviantions)
Packaging (reconcilation)
Storage
Rejected Materials

22. Quality Control Sampling raw materials (active and excipient)
Analytical method testing
Develop and validate quality control methods
Perform stability testing (long term and accelerated)
Available reference materials
Documentation and release of materials and in-process procedures

23. QA Quality Assurance Documents Audit Transport Training Licensing
Warehouse
Packaging QC
Manufacture

24. Quality Assurance Throughout the Manufacturing operations
Documentation
SOP: Authorized, revised periodically updated
Systematic and well kept
Safety and personal hygiene
Training
Monitoring of environmental conditions
Temperature
Humidity
Microbial
Monitoring of processes, personnel, and material flow
Contamination control
Self Audit

25. Engineering- Utilities
Water, Purified and WFI
HVAC
Clean steam
Gases
Compressed air

26. Monitoring system Building management system (BMS)
Environmental management system (EMS)

27. Major Risks in Pharmaceutical Production
Contamination (sources)
Man
Materials
Air
Incorrect labels and containers
Insufficient active ingredient
Excess active ingredients
Poor quality of raw materials
Poor formulation

28. Validation What is validation? What is qualification?
What is calibration?
What is verification?
What is commissioning
What to do?
How to do?

29. Validation
Validation is the action of proving through documented evidence that QC methods and manufacturing processes will consistently yields results that would meet meets their intended result
Application:
QC (Analytical method validation)
Manufacturing (validation of manufacturing processes)
Manufacturing vessels

30. Qualification
Qualification is the action of proving through documented evidence that any equipments and system will consistently perform as their intended use
Application
Production
Utilities QC

31. Calibration
Calibration is the process of comparing a measuring instrument with a measurement standard to establish the relationship between the values indicated by the instrument and those of the standard.
Frequency
Some daily
Some periodically
Some both
What needs to be calibrated
QC measuring instrument, i.e., balance, UV, PH, …

32. Verification
A compendial procedures is considered validated if it is published in USP and BP. Therefore users of such procedures are not required to perform validation studies. But, they must demonstrate the use of these procedures is suitable given the actual conditions of use
Verification is applicable to QC methods

33. Commissioning
Commissioning is the term used for qualifying a new facility before operation starts. The procedures involves qualification of
critical utilities such as HVAC, Water, EMS, temperature, air, pressures …
manufacturing equipments

34. Validation Master Plan (VMP)
Documentation of all validation and qualification activities that identifies scope of work and responsibilities of various departments
It is the regulatory requirement

35. Scope of validation and qualification
Analytical QC method validation (quantitative and qualitative)
Processes validation (mixing & granulation, compression, coating, packaging)
Equipment qualification (oven, compression machine, coating machine, blistering machine, packaging, autoclave….
Cleaning validation (manufacturing vessels)
Computer validation
Utilities (Water, HAVC, environmental monitoring, temperature, pressure, humidity)
Transport validation for cold chain (temperature)

36. Documentation Well documented: Protocol Deviation, if any Report
Sign and approve
Archive

37. Types of Process Validation
Prospective validation (the preferred one).
Validation is done before new product is released for distribution
Retrospective validation (limited use)
Validation based on accumulated historical data

38. Revalidation
As long as the process operates in a state of control and no changes have been made to the process or output product, the process does not have to be revalidated. Whether the process is operating in a state of control is determined by analyzing day-to-day process control data and any finished device testing data for conformance with specifications and for variability.
When changes or process deviations occur, the process must be reviewed and evaluated, and revalidation must be performed where appropriate [820.75(c)]. Review, evaluation, and revalidation activities must be documented.
Processes may be routinely validated on a periodic basis; however, periodic validation may not be adequate. More important is appropriate monitoring so that if problems develop or changes are made, the need for immediate revalidation is considered

39. Food for thought We can not do today’s job with
yesterday’s method and be
in business tomorrow