Global Perspectives In Global Perspectives In Cleaning ValidationCleaning Validation

Presented byPresented by

Bill HallBill Hall

Global Regulatory & Global Regulatory & ComplianceCompliance

►Some things are changingSome things are changing e.g. we now have global guidelines for APIs e.g. we now have global guidelines for APIs

(although there appears to be some (although there appears to be some confusion over who {FDA or industry} is confusion over who {FDA or industry} is going to inspect/audit these mainly foreign going to inspect/audit these mainly foreign facilities)facilities)

►Some things are not changing (or are Some things are not changing (or are changing very slowly)changing very slowly) e.g. don’t yet have global GMPse.g. don’t yet have global GMPs

Why are global GMPs so Why are global GMPs so significant?significant?

►Everyone on the same pageEveryone on the same page►Minimize culture effectsMinimize culture effects

e.g. single signatures of critical steps in e.g. single signatures of critical steps in Europe and double signatures of critical Europe and double signatures of critical steps in USsteps in US

Speaking of Global, as in Speaking of Global, as in CompetitionCompetition

““China is expected to become the fifth China is expected to become the fifth largest pharmaceutical market in the largest pharmaceutical market in the world, doubling its present $12 billion in world, doubling its present $12 billion in sales by the end of the decade”.sales by the end of the decade”.

““Until recently, China’s pharmaceutical Until recently, China’s pharmaceutical industry has largely focused on generic industry has largely focused on generic manufacturing and counterfeiting of brand manufacturing and counterfeiting of brand name drugs.name drugs.

“ “ But now the Chinese pharmaceutical But now the Chinese pharmaceutical industry is shifting from imitation to industry is shifting from imitation to innovation, with more than 5000 research innovation, with more than 5000 research and development institutions including 500 and development institutions including 500 to 1000 biotech companies. More than 20 to 1000 biotech companies. More than 20 biotech parks can be found throughout the biotech parks can be found throughout the country”country”

And finally, regarding ChinaAnd finally, regarding China

““More than 3700 manufacturers are More than 3700 manufacturers are certified in Chinese Good certified in Chinese Good Manufacturing Practices (GMP) Manufacturing Practices (GMP) standards”standards”

Technology is changingTechnology is changing

►More technical tools are availableMore technical tools are available Near IR for sampling/IDNear IR for sampling/ID Airport scanning devices have been Airport scanning devices have been

considered for cleaning validation considered for cleaning validation (advantage is speed of determining (advantage is speed of determining whether surfaces are truly clean) but have whether surfaces are truly clean) but have not worked out in actual practice in not worked out in actual practice in pharmaceutical applications so farpharmaceutical applications so far

Total Organic Carbon-is being used widely Total Organic Carbon-is being used widely for water analysis and cleaning validation for water analysis and cleaning validation studies especially for cleaning agentsstudies especially for cleaning agents

Speed of AnalysisSpeed of Analysis

►Time is moneyTime is money►Time is also delaying justiceTime is also delaying justice

North Carolina currently has such a large North Carolina currently has such a large backlog of samples in the labs of the State backlog of samples in the labs of the State Bureau of Investigation (SBI) that habitual Bureau of Investigation (SBI) that habitual felons are having to be released and then felons are having to be released and then are being rearrested multiple times for are being rearrested multiple times for committing additional felonies while committing additional felonies while awaiting trial. (Trial cannot proceed until awaiting trial. (Trial cannot proceed until all evidence, including lab analysis, is all evidence, including lab analysis, is available)available)

Excerpt from Excerpt from Drug Discovery &Drug Discovery & Development Development (February 2006)(February 2006)

►Title of Article = “Crafting Smaller and Title of Article = “Crafting Smaller and Faster Technologies”Faster Technologies”

►““The high-throughput mass The high-throughput mass spectrometry (HTMS) system allowed spectrometry (HTMS) system allowed them to cut sample preparation time them to cut sample preparation time from 30 seconds to 3 seconds.”from 30 seconds to 3 seconds.”

►““Everything boils down to speed”Everything boils down to speed”

Additional quotes from same Additional quotes from same articlearticle

““The Ultra Performance LC was designed The Ultra Performance LC was designed from the ground up to reduce run from the ground up to reduce run times by up to 10 times using low-times by up to 10 times using low-dispersion, high speed detectors and dispersion, high speed detectors and 1.7 1.7 µm small particle chemistries for µm small particle chemistries for columns”columns”

andand

““The chemists come up and say they The chemists come up and say they now try things that they’ve never tried now try things that they’ve never tried before or hardly ever tried before before or hardly ever tried before because of time constraints and because of time constraints and because of the cost of the compound because of the cost of the compound to run a reaction on a certain scale to run a reaction on a certain scale and have it fail.”and have it fail.”

In my opinionIn my opinion

► It is time to “steal” technology from It is time to “steal” technology from other industries just as we took dust other industries just as we took dust collectors (Toritscollectors (Torits®®) from the lumber ) from the lumber industry and clean-in-place (CIP) industry and clean-in-place (CIP) technology from the dairy industrytechnology from the dairy industry

►Specifically, I’m speaking of applying Specifically, I’m speaking of applying bioluminescence (ATP ADP + bioluminescence (ATP ADP + light) from the food industry and apply light) from the food industry and apply it to pharmaceutical surfacesit to pharmaceutical surfaces

Microbial AnalysisMicrobial Analysis

►Has always been slow (by the time we Has always been slow (by the time we get the results of our water testing it is get the results of our water testing it is too late to do anything about it)too late to do anything about it)

►We need to borrow the new We need to borrow the new bioluminescent technology being used bioluminescent technology being used by the food industry to evaluate by the food industry to evaluate cleaned surfaces in restaurants and cleaned surfaces in restaurants and food preparation areas for microbial food preparation areas for microbial levelslevels

APIs, Contaminants, Counterfeiting, APIs, Contaminants, Counterfeiting, and Bioterrorism Issuesand Bioterrorism Issues

►Cleaning or contamination issues are Cleaning or contamination issues are potentially very great in our raw potentially very great in our raw materials. materials. Why can they make the APIs so cheaply in Why can they make the APIs so cheaply in

other countries? (This is an era where we other countries? (This is an era where we can buy mfging equipment on e-bay)can buy mfging equipment on e-bay)

How good are we at detecting contaminants How good are we at detecting contaminants in our raw materials, particularly bioactive in our raw materials, particularly bioactive or highly toxic impurities? Are our assays or highly toxic impurities? Are our assays (which are based mainly on assay of (which are based mainly on assay of known known constituents) good enough in all cases?constituents) good enough in all cases?

Some Myths in Cleaning Some Myths in Cleaning ValidationValidation

(Reference: Destin LeBlanc, PharmTech Europe, Dec (Reference: Destin LeBlanc, PharmTech Europe, Dec 2005 and Feb 20062005 and Feb 2006

1.1. Regulatory authorities do not like Regulatory authorities do not like rinse samplingrinse sampling

2.2. You must correlate rinse sampling You must correlate rinse sampling results with swab sampling resultsresults with swab sampling results

3.3. You cannot use nonspecific analytical You cannot use nonspecific analytical methodsmethods

4.4. If you use total organic carbon (TOC) If you use total organic carbon (TOC) you must correlate it with a specific you must correlate it with a specific method such as HPLC method such as HPLC (continued on next slide)(continued on next slide)

Some Myths in Cleaning Some Myths in Cleaning Validation Validation (continued from previous slide)(continued from previous slide)

5.5. Any measured residue is Any measured residue is unacceptableunacceptable

6.6. Dose-based calculations are Dose-based calculations are unacceptableunacceptable

7.7. Recovery percentages of different Recovery percentages of different spiked levels should be linearspiked levels should be linear

8.8. You cannot validate manual cleaningYou cannot validate manual cleaning

►Thanks very much !Thanks very much !

►Questions?Questions?