World Health Organization Pharmaceutical Development 17 April, 2017 Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007

Pharmaceutical Development World Health Organization Pharmaceutical Development 17 April, 2017 Good Manufacturing Practices (GMP) and Inspections Presenter: Dr AJ van Zyl Prequalification Programme: Priority Essential Medicines, HTP/PSM/QSM World Health Organization, 20 Ave Appia, 1211 Geneve, 27 Switzerland vanzyla@who.int

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Outline and Objectives of presentation Introduce WHO GMP texts Main principles Supplements Others In the context of Prequalification Current and future approaches

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 WHO GMP text: Main principles WHO Technical Report Series, No. 908, 2003 Annex 4 Regularly reviewed and updated Divided into "chapters" or "quality systems" Quality assurance

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 1. Quality assurance 2. Good manufacturing practices for pharmaceutical products (GMP) 3. Sanitation and hygiene 4. Qualification and validation 5. Complaints 6. Product recalls 7. Contract production and analysis 8. Self-inspection and quality audits

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 9. Personnel 10. Training 11. Personal hygiene 12. Premises 13. Equipment 14. Materials 15. Documentation 16. Good practices in production 17. Good practices in quality control

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Supplements: Sterile products Herbal medicines Radiopharmaceuticals HVAC Water systems Sampling etc

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Others: PIC/S guidelines ISO guidelines Sampling Risk management Clean rooms ICH guidelines ICH Q9 USA FDA Guidelines and guidance

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Context in Prequalification Product specific (dosage form) inspections SOPs followed: Planning, preparation, conduct, report Inspection team Appropriate guidelines used Report with references to text, and rating Critical, major, minor

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 A critical deficiency was defined as a deficiency which had produced, or led to a significant risk of producing, either a product which was harmful to the human patient or a product which could result in a harmful residue in a food producing animal. A major deficiency was defined as a non-critical deficiency, which had produced or might produce a product which did not comply with its marketing authorisation. A minor deficiency was defined as a deficiency where an observation made could improve the quality system and quality assurance approach of the manufacturer, but which did not have a major impact on the quality of the product.

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Inspection approach Normally a "routine type" of GMP inspection Opening meeting, follow the flow, closing meeting On site inspection (production and quality control) and documentation review Quality systems approach Modern challenges including risk assessment

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Guiding principles: Risk based orientation Science based policies and standards Integrated quality systems International standards Public interest

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Product quality and performance ensured through design (manufacturing processes) Product and process specifications Understanding of affect of formulation and process factors on product quality and performance Quality by design (build quality into the product) Interaction between review, compliance and inspection

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Quality by design (QbD) Means designing and developing formulations and manufacturing processes to ensure predefined product quality Understanding and controlling formulation and manufacturing process variables affecting the quality of a product

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Where to start in the inspection to assess GMP compliance?

World Health Organization Premises World Health Organization 17 April, 2017 Example of Materials and People Flow Arrival of goods Entrance for visitors Entrance for Workers Shipment of goods Material Flow People Flow Zone: Clean Zone: Packaging Zone: Controlled This sheet shows the flow of material and personnel. The green arrows indicate the material flow, and show materials that are brought in each room through the corridor zone. The cubicle between the corridor and the work zone may be an airlock, but in some countries this is required to be an air shower. The red arrows indicate the people flow and show how people enter each room through the corridor divided by the zones.

Premises and personnel entry World Health Organization 17 April, 2017 Explain the layout of change rooms, washing facilities and toilets. Explain the importance of hygiene

World Health Organization Material entry World Health Organization 17 April, 2017 Separate receiving and dispatch bays Materials and products protected from weather Area to clean incoming materials provided Separate receiving and dispatch bays are recommended and materials and products should be protected from weather (rain, sun etc). An area to clean incoming materials and containers should be provided.

Basic Principles of GMP World Health Organization 17 April, 2017 Discuss the: issuing of materials, reconciliation, storage and transport in closed containers to prevent mix-ups

Equipment Contents and direction of flow indicated e.g. water lines, equipment components, air-handling systems

World Health Organization Equipment World Health Organization 17 April, 2017 All aspects including Design, installation, operation, performance, specifications, logs, maintenance, use, cleaning, qualification, calibration etc… Discuss the aspects of the fluid bed dryer such as: Procedures and records for qualification, Quality of inlet air and air out to the atmosphere, filtration levels, Controllers and recorders e.g. temperature (inlet and outlet), Calibration, PLC, FBD bag (dedicated or not, Cleaning of the FBD and the bag, including drying after cleaning, FBD bowl and integrity checks, Air volume, pressure .

Qualification and Validation World Health Organization 17 April, 2017 Discuss dispensing of materials

World Health Organization 17 April, 2017 Documentation During inspections, you can also verify the documents against actual instruments, equipment, premises etc. You have to verify that the documents are accurate, and current. Check the drawings against the qualification reports and proof of components. If any changes were made, did these go through a change control procedure? Was requalification required and done?

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Utilities HVAC Water Compressed air Steam . . .

World Health Organization 17 April, 2017 HVAC Prefilter Air flow patterns AHU Main filter Uni-directional Turbulent 1 2 3 This slide shows an HVAC installation feeding 3 rooms, each one with terminal filters, all terminal filters protected by a remote pre-filter. Room 1 has a turbulent air flow, with low level exhaust. Room 2 has a uni-directional air flow, over the largest part of the surface, hence the large number of filters, with low level air returns. Due to the high cost of the ventilation in class A areas, the tendency is to keep these areas as small as possible. Room 3 has a turbulent air flow, with ceiling exhaust. Good design practices recommend that cleanrooms A, B and C (ISO Class 5, 6 & 7) should have low level air returns.

World Health Organization 17 April, 2017 HVAC Main subsystems + Production Room Exhaust air treatment Central air handling unit Terminal air treatment at production room level Fresh air treatment (make-up air) To understand the air handling systems, it is necessary to know what their components are. A conventional Air Handling System has 4 sub-systems: 1. Air handling of the incoming (fresh) air: elimination of coarse contaminants and protection from frost if necessary. In the case of air re-circulation, the fresh air is also called make-up air. 2. Central air handling unit (AHU), where the air will be conditioned (heated, cooled, humidified or de-humidified and filtered), and where fresh air and re-circulated air, if any, (indicated here by the dotted line) will be mixed. 3. Air handling in the rooms under consideration (pressure differential system, additional filtration, air distribution). 4. Air exhaust system (filtration).

World Health Organization 17 April, 2017 HVAC Qualification – examples of aspects to consider in qualification (OQ, PQ) Test Differential pressure on filters Turbulent / mixed airflow Description Uni-directional airflow / LAF Room differential pressure Airflow velocity / uniformity Airflow volume / rate Parallelism Air flow pattern 2 N/A 2, 3 Optional 3 1 := As built (ideally used to perform IQ) 2 = At rest (ideally used to perform OQ) 3 = Operational (ideally used to perform PQ) This slide shows a series of tests to be carried out during qualification. There are different tests for the turbulent and for the uni-directional air flows. The differential pressure on filters is an indication of the clogging of the filters: with the charging of dust on the filters, the differential pressure will increase. In order to keep the volume of air constant, the fan speed may increase, with the following consequences: Damage to filters, and passage of unfiltered air Particles and micro-organismes will be “pushed” through the filter units. (Inspectors should check whether pressure differential manometers are installed on the AHUs. Without this means of monitoring the filters, the system could go out of control causing contamination problems.) Airflow patterns are interesting to visualize (smoke tests), as zones without proper flushing can be easily identified. It is also important to monitor air flow velocities for each HEPA filter according to a program of established intervals because significant reductions in velocity can increase the possibility of contamination, and changes in velocity can affect the laminarity of the airflow. Airflow patterns should be tested for turbulence, as these can interfere with the flushing action of the air.

World Health Organization 17 April, 2017 Water for Pharmaceutical Use raw water in « S” trap to sewer Water is kept circulating To water softener & DI plant Pretreatment – schematic drawing cartridge filter 5 micrometers activated carbon spray ball break tank air break to drain centrifugal pump air filter float operated valve sand filter excess water recycled from deioniser This schematic drawing is shown in handout 2-1-21 and illustrates a typical storage and preliminary treatment system for water. Raw water arrives into a buffer or break tank via a level controlled valve. If there are further stages of treatment (such as DI or RO), the tank does not, generally, have to have sophisticated spray balls or air filters. The water is pumped through a sand filter to remove large particles. This filter must be fitted with a back-flush facility, not shown here. The water then enters an activated carbon (AC) filter which removes organic impurities and chlorine. The AC filter can become heavily contaminated with bacteria. There should be some means of sanitizing it, such as a steam supply. Chemicals are generally not used to disinfect activated carbon filters. The water is then “polished” through a 5 micron filter before it enters the next treatment step. If there is no demand for the water it must be re-circulated to the buffer tank. Water that is kept constantly circulating is less likely to grow bacteria, because they cannot settle and form a “biofilm”. All equipment such as pumps, pipes and tanks should be stainless steel wherever possible. Plastic should be avoided. Plasticizers may leach and this can result in out-of-specification Total Organic Carbon (TOC) levels. Adhesives used for welding plastic pipes may also leach into the water and cause problems.

World Health Organization Quality Control 17 April, 2017 Separate guideline in addition to basic GMP Part 1: Management and organization Part 2: Materials, equipment, instruments and devices Part 3: Working procedures and documents, and safety in the laboratory Part 4: Inspecting the laboratory

World Health Organization Quality Control World Health Organization 17 April, 2017 Dissolution Testing errors are caused by: Temperature variations Rotational speed variations Vibration Wobble Shaft perpendicularity Tension on the chain or belt Bubbles Shaft centering Dissolution (contd): Testing errors will all make the product appear to perform better than it is. They include factors such as: Influence of temperature: The thermal distribution profile of the water bath should be checked. Note that turbidity in the water could indicate growth of bacteria Rotational speed: Check calibration with a tachometer. Sources of vibration: Vibration causes turbulence. Sometimes a shock absorbing rubber mat is used under the apparatus and the drive unit may have good vibration-limiting shock absorbers. Shaft wobble will mean turbulence. Shaft Perpendicularity: Check with a spirit level and a builder’s square. Tension on the chain or belt. Looseness will mean speeding up and slowing down leading to turbulence. Bubbles: Can create turbulence. Acid on unprotected steel (even stainless steel) can lead to bubbles of hydrogen gas. Shafts must be centered with respect to the vessels.

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Quality control (also micro, water, environment…) Sampling and testing Reference Standards Specifications Stability testing Source/raw data Qualification and validation

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Other aspects to look at include: Validation (process, cleaning etc) CAPA, failure investigation Change control Deviations Complaints Product quality review

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Unlimited resources ? Inspectors ? Days ? Guidelines ?

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Planning and conduct of inspection Type of product(s) Type of material(s) Premises Changes (deviations, additional products, cleaning procedure, campaigns etc) Utilities and applications

Formal process of risk management Ref. ICH Q9, Quality Risk Management

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Summary GMP remains important component of ensuring QA and quality New approaches in quality (including risk management, CAPA, PAT) Impact on total approach including Product design, product development, pilot batches, production batches Quality systems and quality assurance

Good Manufacturing Practices (GMP) and Inspections World Health Organization Good Manufacturing Practices (GMP) and Inspections 17 April, 2017 Acknowledgements WHO Training modules Basic and supplementary ICH Q9 S Galson and LX Yu (USA FDA presentations)