Risk Analysis: myths, confusions and real sense

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Godwin Shon Watson
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1 Risk Analysis: myths, confusions and real sense Dr. Alexander Fedotov, Director of Invar-project Company, Moscow, Russia 1. What is risk analysis? 2. GMP EU and ICH Q9 promises 3. : comparisons of incomparable 4. Example for pharmaceuticals 5. Inspections and Delayed-action Mine Rational sense of risk analysis 2 What is Risk analysis? - Risk means the possibility of dangerous or unwanted event to occur; - People analyze risk for ages and every day to be protected against unwanted events; - Purpose is to understand chain: Reason Defect of tablet press punch, for example Event Break of punch Consequence for product Metal parts in the tablet 3 GMP EU and ICH Q9 promise : ICH Q9 Quality Risk Management ; : ICH Q9 became Annex 20 GMP EU; : it became Part III of GMP EU Introduction to GMP EU says: The aim of Part III is to clarify regulatory expectations and it should be viewed as a source of information on best current practices. 4 GMP EU and ICH Q9 promises Batch recall - Methods of risk managements are separated on general and other ; - General methods include: Flow charts; Check sheets; Cause and Effect diagram (Fishbone or Ishikawa diagram); and others. 5 Premises and equipment Quality control Documents Personnel Media Materials Process in Contaminants APIs Washing of vials WFI analysis Excipients Sterilizing of vials Mix-ups Vials Fault tree or Block-scheme 6 1

2 Example of Out-of-Specification Table Materials, process etc. Reason When/how it appeared 1 Materials - API Contamination July 20 Batch numbers recalled and actions Changing of supplier - excipients vials Damage of external March 20 The instruction was done to forwarding company packaging - stoppers caps Personal -contamination Wrong behavior May 20 The SOP was reviewed, secondary training and control of behavior -mistakes mixings Equipment 7 Washing of vials Vials Sterilizing of vials Process Materials Excipients API s WFI Media Contaminants Personnel Mix-ups Documents Quality control Premises and equipement in analysis Fishbone or Ishikawa diagram (offered in 1952) Product recall 8 EU GMP and ICH Q9 promise - Other methods include: FMEA, FMECA, HACCP and so on abbreviations. - Let s look how they work on example of FMEA (Failure Mode Effect Analysis) method that is propagated widely; - Others are similar. 9 It is stated that FMEA gives Quantity estimation of risk making following: 1st Step. All risks shall be grouped on evaluation criteria: - Severity/Impact (I); - Occurrence or estimation of probability of event (O); - Detectability (D). 10 2nd Step - Each of criteria has numerical value, - For example, numbers from 1 to 5, - 1 means the lowest risk and 5 means the highest risk. 3d Step - Risk Priority Number (RPN) is calculated by multiplying evaluation criteria: I O D; - RPN range is from 1 (when all criteria are 1) to 125 (when all criteria are 5); - RPN grows with increasing of risk

3 4th Step - Acceptance level of RPN shall be specified in advance; - It can be any number within RPN range (1-125), say, 27; 51 or 109; - It is assigned arbitrary, just by opinion of one or several persons. - If RPN < Acceptance level, then risk is low; - No further action needs to be implemented; - In contrary if RPN > Acceptance level, correction actions are needed FMEA has three fundamental mistakes: 1st mistake - Acceptance levels (and RPN) are assigned by human arbitrary or subjectively, by his own mind; -Thisarbitrary estimation serves further as a basis for responsible decision. It is a very dangerous approach! 15 FMEA: comparisons of incomparable 2nd mistake - Values with different sense (I; O; D) are multiplied; - result serves as a basis for conclusion; -To compare incomparable is a huge and obvious methodical mistake; - It is not possible to multiply values with different sense. 16 3d mistake - Arbitrary numbers are offered to estimate processes - evaluation criteria; - Mathematical play with RPN gives image of Quantity analysis only; - Arbitrary estimation whether RPN can be accepted or not. This play has nothing common with science FMEA Example: Two events for airplane Event Delay of plane arrival Crash of plane Severity Evaluation criteria Occurrence Detectability RPN Delay and Crash are equivalent by FMEA - Is it better than discussions of medieval monks from Thomas Aquinas times: How many devils can be accommodated on the tip of the needle?

4 Process step or equipment preparation preparation preparation Loading Automatic loading adjustment IPC Etc. FMEA - Example for pharmaceuticals Ac. Level=27 Possible failure/risk Cleaning not sufficient Recalibration interval violated Punches installed not correctly Consequence of failure Cross contamination/ microbiological contamination Occurrence Severity Detection RPN Further action Yes/No No No GMP conformity No Tablets contaminated (metal) machine defect, loss of production No Not enough No delivery of No loading goods granules for the compression process Wrong Patient dead No granules Wrong Tablet content too No Adjustment high, patient harm Balance wrong Wrong weight, Patient harm No ICH Q9 (Part III of EU GMP) says that it helps manufacture and inspector How it helps manufacture? - Does it help to construct process flow charts, to find critical points, to draw HVAC, WFI and other schemes? No! - They all shall be in the design! - To arrange routine testing/control and to write documents? But is already in GMP! 20 Risk analysis helps inspector How? One of inspectors writes: - Inspector has not enough time and cannot see all details; - Papers on risk analysis prepared by manufacturer make the inspector s task easier to understand work of the plant. Inspections and Delayed-action Mine It is a very important opinion: - Inspector observes not primary documents (WFI schemes, records, etc.); - but secondary ones, i.e. papers that reflect primary sources only partly; - prepared by persons to be inspected. A fundamental danger is hidden in this approach! Inspections and Delayed-action Mine It would be interesting to look: -How financial/tax inspector will check the company on interpretations of financial documents made by people under inspection, not on the very documents; -How road police will judge guilty drivers on driver s own interpretation of accident; - and so on. Inspections and Delayed-action Mine - Customer buys medicinal product that shall comply with primary documents not with exercises; - It cannot be allowed to evaluate manufacturer by extracts from documents or comments, especially made by persons under control. This is a Delayed-action Mine!

5 End of 1940s 1) New systems and their low reliability: - about 70 % Navy radio-electronic devices of US armed forces were inoperable because of malfunctions; - 50 % of equipment and spare-parts failed during storage in warehouses; -First computers could work without failure only a few hours/minutes. 25 2) Strong stress: - The Cold War and fear of global disaster; - But very responsible technical systems simply did not work; 3) It was a romantic period: Cybernetics and other sciences appeared. They planted trust that any problem can be solved with magic general methods without knowing it in-depth 26 - It is not a surprise that those who offered methods of solving all problems got immediate support; - They simply found themselves in right place and in right time; - Just a promise to solve problem ensured budgeting on trust only; - Risk analysis was among such applicants FMECA method was approved by US Ministry of Defense in 1947; - And high prestige of this Ministry started to work on methods of risk analysis; - Nobody noticed fundamental mistake of this method that compares incomparable. Start of cybernetics planted in mind seeds of hope that there can be general methods to analyze the problem without knowing it s - Risk analysis was widely discussed together with reliability and models; - As a result formal methods were rejected; - Problems shall be understood in-depth; - Facile or wrong advices are not needed. US Ministry of Defense cancelled FMECA in It is hardly believable that such Ministry could withdraw useful document s - Risk analysis businessmen understood that they have nothing to do in technical industries; - They came to food industry; - It was a great success for them; - Business to exploit trust of people in scientific-like methods gave great profit. 30 5

6 Pharmaceutical industry is the next; - We observe very well conducted company to occupy rich markets: - ICH Q9 information only, - Annex 20 GMP EU recommended, - Part III GMP EU more important. Pressure grows! 31 Risk analysis Danger of formal approach Why are we so anxious? -Time and human resources in real manufacturing life are always limited; - Plays with formal methods can distract attention from care on quality; - Methods can serve as excuse for risk It breaks the main condition: No risk for medicines is permitted! 32 Can Risk analysis can be positive? - Yes, if it professional, clear and useful. Example of Company Nutricia - In 1993 the batch of product contained residues of disinfectants was recalled from the market; - This accident pressed company to implement Risk analysis system. 33 Real sense of risk analysis is to show how facility is protected against (design): - Cross contamination (layouts; airflows; pressure differences; materials, personel etc. flow and so on); - Mixing of materials and products; - Mixing of sterile and non-sterile products; - Non-sterility in aseptic processes; - Contamination (particles, viables ); - Surfaces contamination; - design 34 Operation: Experience of Nutricia Thinking approach was applied that was focused on the sense of matter: - 36 risk analysis groups were arranged at the head factory; - 20 % of factory s personnel were members of these groups; - mean number of persons in group was 5; Experience of Nutricia - Weekly short meetings of each group; - Internal audits (self-inspections); - Analysis of customer s complaints; - Inspections of suppliers systematically; -Factory s data base on contamination was arranged and it is continually supported and revised

7 Experience of Nutricia Soon problematic places were revealed: - personnel; - contamination; - raw materials defects; - out-of-standards deviations. It is very close to problems of pharmaceutical factories. 37 Conclusion 1. Method has no right to exist in two cases: - if it is wrong and misleading for users; - if it gives trivial result (result that can be got by simpler way or is obvious). ICH Q9 methods fall under these two cases and are not suitable for use. 38 Conclusion 2. Special danger of methods enforced is that they allow unacceptable events. These methods, moving from the office to manufacture can be used by somebody to justify wrong work. 3. Science says that we belong to creatures named Homo sapience or Wise man. If so, why do we accept exercises like FMEA method? Conclusion 4. Everybody speaks about manufactures, inspectors and consultants. - What about customers, who the main party? - What can be their reaction on ICH Q9 and similar methods? 5. It is necessary to arrange wide discussion on Risk analysis methods with all pro and contra to form public opinion Thank you for your attention! 41 7

WHO guidelines on quality risk management

Annex 2 WHO guidelines on quality risk management 1. Introduction 62 1.1 Background and scope 62 1.2 Principles of quality risk management 64 2. Glossary 67 3. Quality risk management process 70 3.1 Initiating