Inspections and Risks: A Regulatory perspective on Aseptic Processing

1
Inspections and Risks A Regulatory perspective
on Aseptic Processing

• Paul Hargreaves
• Inspection Enforcement Division
• Medicines and Healthcare products Regulatory
  Agency
• United Kingdom

2
What is a risk based inspection?

• Aseptic processing is by definition a high
  risk
• a risk for the patient in terms of infection
• a risk to the company in terms of rejection rate
  and adverse publicity

3
Risk based inspections

• A risk based inspection consists of two
  components
• The company
• The process
• Whilst this presentation concentrates on the
  process (aseptic processing) I will spend a few
  minutes describing a risk based company
  inspection.

4
Company risk based inspection

• What signals do we look for?
• Rule of Thumb The number of times company
  personnel say Quality in a sentence is
  inversely proportional to the quality of their
  quality system.
• Example We believe in quality and ensure that
  our customers only receive a quality product
  manufactured under our strict quality policy to
  the highest quality standards.

5
Risk based inspections

• This is a real example, and during inspection we
  found that Quality was a marketing term and did
  not reflect the actuality.
• Many critical deficiencies were identified as
  there was not a robust quality system in place.
• Positive signal A company that has a mature and
  well implemented quality system in place does not
  mention Quality as it is a given (assumed).

6
Other Signals

• Many companies do not recognise the other signals
  they give to Regulatory Authorities which
  identify them as High Risk.
• Marketing led companies
• Batch out of specification OK what market will
  accept it? We receive complaints from
  regulatory authorities when Agents try to sell
  OOS products in their countries.

7
Other Signals

• Production led companies
• Manufacturing do everything environmental
  monitoring, validation, investigations, problem
  solving etc.
• Quality Assurance are just a token to rubber
  stamp everything that manufacturing do and give
  it some legitimacy.

8
Other Signals

• Personality led companies
• Strong personality overrules role function.
• Role clarity not clear within the company.

9
Other Signals

• Regulatory Dept. located and seen as a Head
  Office function
• Poor communication with QA, QC and manufacturing
• Leads to significant discrepancies with the
  Marketing Authorisations and failure to meet
  post-marketing commitments.

10
Risk based inspections

• Risk assessment based upon previous inspections
• Systemic weaknesses identified over a period of
  years
• In depth inspection of previously identified
  weaknesses
• May identify Critical or Major Deficiencies

11
Risk based inspections

• Risk assessment based upon knowledge of common
  aseptic processing issues
• Inadequate environmental monitoring programmes
• Inadequate control over equipment autoclave
  sterilisation cycles
• Inappropriate behaviour in clean rooms

12
Risk based inspections

• Inadequate sanitisation of equipment, tools and
  utensils into the clean room
• Changing rooms being too small with inadequate
  segregation
• Inappropriate process and personnel flow
• Single door autoclaves instead of double door

13
Risk based inspections

• An inspector may use one or the other techniques
  but usually a combination of both during an
  inspection
• The inspector is looking to find Critical
  deficiencies on Day 1, Major on Day 2 and Other
  on Day 3.
• Long gone are the days of a general inspection
  - the inspector is focussed on risk and is
  trained to do this.

14
The Big Issue

• Many companies, large and small collect a large
  amount of data.
• What they fail to do is to convert data into
  information.
• If they had information they could then convert
  this into knowledge about the process.

15
What is information and knowledge?

• Data is pages and pages of results
• Information is, for example, trending the results
• Knowledge is about having a thorough
  understanding of the whole process. This is what
  PAT is all about - converting data into
  knowledge.

16
What is the role of PAT in aseptic processing?

• The principles are the same
• A settle plate or contact plate can provide as
  much information as a NIR spectrum - it is how
  you process the data that counts.
• Its not just numbers - its species and how they
  got into the clean room and from where that
  counts.

17
The sum total

• Risk is cumulative
• Silo mentality
• Each manufacturing department knows there is a
  problem but nobody can see the big picture
• Minor problems in each Dept. cumulatively add to
  Major and eventually Critical deficiencies.

18
The sum total

• Why does the inspector identify the sum total
  problem and not the company?
• We need to look at how an inspector works

19
MEDIA PREPARATION

• High quality microbiological growth medium,
  prepared to the highest standard is critical.
• The whole of the monitoring programme is
  dependant upon this.
• There is little point in examining monitoring
  data without first inspecting media preparation.

20
TSB
Tube B
Tube A
Which tube of TSB is unsuitable for use and why?
21
WHAT INSPECTORS LOOK FOR

• Overcooking of media (some media have to be
  heated to dissolve it).
• Excessive autoclave cycles. A target of Fo 8.
  The standard cycle of 15 min. at 121 deg.C will
  give Fo 25.
• Media pH not checked after autoclaving.
• Autoclave not validated.
• Different size containers in the load.

22
WHAT INSPECTORS LOOK FOR

• Same containers used for selective media
  (contains antibiotics, inhibitors, etc.) and
  growth promoting media.
• Same for tubing used in peristaltic pumps for
  dispensing media.
• At one site, management could not find the media
  preparation area!!

23
WHAT INSPECTORS LOOK FOR

• Water used to reconstitute media heavily
  contaminated with micro-organisms (bacteriocins,
  exotoxins, etc. inhibit growth).
• Algae in water storage container tubing.

24
FERTILITY/GROWTH PROMOTION TESTS

• Test results may be used as an excuse for poor
  media preparation or the use of inappropriate
  media.
• This test uses very healthy strong laboratory
  strains that will grow on poor quality or
  inappropriate media.
• Microbiological monitoring is meant to detect
  physically metabolically injured cells.

25
FERTILITY/GROWTH PROMOTION TESTS

• Environmentally damaged cells will only recover
  grow on high quality media.
• No quantitative limits for fertility test.
  Qualitative limit (growth/no growth is not
  acceptable)
• Expiry date of media not validated.
• Growth promotion capability decreases rapidly in
  first week after preparation.

26
FERTILITY/GROWTH PROMOTION TESTS

• Stabilises after 1 week for 1 month then
  rapidly declines further.
• Ive seen expiry dates of up to 1 year based upon
  the fact that the plates have been irradiated!
  No account taken of growth promoting capability.
• Irradiated media should contain free radical
  scavengers and anti-oxidants.

27
TESTING PRACTICES or How to obtain Zero Results?

• It is very easy to obtain zero results in all
  microbiological monitoring, including sterility
  bioburden testing.
• If there are find pages pages of zero results
  this should ALERT you NOT satisfy you.

28
HOW TO OBTAIN ZERO RESULTS

• In clean rooms
• Position plates directly under HEPA filters
• Position plates well away from human activity
• Use old plates that are dehydrated
• Do not monitor filling machine set-up
• Do not use Sabouraud Dextrose media when fungal
  spores are likely to be present
• This is how pages pages of zero results are
  obtained.

29
HOW TO OBTAIN ZERO RESULTS

• In water testing
• Run water at the test point for 5 min.
  (Production wont do that)
• Store the water sample as long as possible before
  testing (cells attach to container walls)
• Use the pour plate method
• Use the incorrect medium

30
ZERO RESULTS
31
ZERO RESULTS

• Clinicians have long been aware of human
  diseases associated with viable but
  non-culturable micro-organisms.
• Biofilm mass contain only 1 to 15 culturable
  micro-organisms and so the underestimate by
  traditional tests is significant.
• Recovery from water samples is in the region of
  only about 0.25.

32
L- forms of bacteria - Another hazard for the
patient!

• L-forms lack cell walls and consist of highly
  pleomorphic elements ranging in size from 100nm .
  to 800nm.
• They form and grow in interstitial spaces such as
  found in filters and membranes (c.f. recent paper
  on filters in water systems).
• There is evidence that L-forms may act as the
  primary aetiological agents in infectious
  diseases and, in particular , may be responsible
  for relapse after apparent cure. (Thomas, A.J.
  Pharm. Tech.)

33
L- forms of bacteria - Another hazard for the
patient!

• L-forms of Pseudomonas aeruginosa have been
  isolated from clinical specimens of sputum, pus
  and urine.
• The evidence for the spontaneous formation of
  wall-defective microbial variants of Pseudomonas
  aeruginosa in filtration systems has therefore
  been demonstrated as the cause of filter failures
  during these bacterial challenge studies.
  (Thomas, A.J. Pharm. Tech.)

34
ASEPTIC FILTRATION

• Absolute filters?
• 0.2 micron filters?
• Sterilizing filters?
• Passage of Ps. Pickettii thru
• 0.2 filter.
• Isolate from commercial 0.9
• Saline placed on the market -
• infected neonates.

35
ZERO RESULTS

• In the sterility test
• Allow the membrane filter to dry out under vacuum
• Place filter in the oxidised layer of
  Thioglycollate medium
• Use old Thioglycollate that is fully oxidised

36
Thioglycollate mediumSterility test
No oxidation
Oxidised layer pre-incubation
Oxidised layer post-incubation
37
Thioglycollate mediumSterility test

• What are the Ph. Eur. limits for maximum
  permitted levels of oxidation
• Pre-incubation?
• Post-incubation?
• Where should the membrane filter be placed in the
  tube
• Top?
• Middle?
• Bottom?

38
Thioglycollate mediumSterility test

• What is the name of the indicator used in
  Thioglycollate to indicate oxygen uptake?
• What colour is it in the oxidised state?
• Is Thioglycollate available without the
  indicator?

39
What does the inspector look for?

• Bad practices
• See the monitoring locations for themselves
• Inspect media preparation
• Does not rely upon the results - checks first
  whether the results are reliable

40
Moving on

• Another current and ongoing issue is the
  inadequate validation of equipment sterilisation
  used in aseptic processing.
• Validation data often shows that either the
  autoclave is defective or
• The cycle used is inappropriate (lack of air
  removal and/or lack of steam penetration into the
  equipment)

41
How has this situation arisen?

• Reliance upon biological indicators and Fo to
  validate the cycle
• Ignoring the thermometric data that conclusively
  demonstrates a significant problem
• Non-recovery of a BI does not mean the BI has
  been killed! At best it demonstrates that a heat
  damaged BI has not been able to recover under the
  conditions used.

42
The misuse of the Fo concept

• Fo is only valid when the microenvironment can be
  guaranteed, i.e. in a closed container
• ampoule/vial
• bag
• tin of baked beans (Fo originated from the food
  industry)

43
The misuse of the Fo concept

• The microenvironment inside an equipment load
  cannot be guaranteed because it relies upon
• adequate air removal
• adequate steam penetration
• lack of leaks in the autoclave (door seal,
  valves, pipework)
• prevention of introduction of non- condensable
  gases from the steam supply
• prevention of condensate accumulating in
  equipment

44
Draft 14 of the PDA Monograph No.1

• Unfortunately, this Draft does not take adequate
  cognizance of European, International and
  American National Standards with regard to these
  critical factors.
• Reliance upon inherently variable biological
  systems rather than hard science (the laws of
  physics) does not comply with EU GMP.

45
AUTOCLAVE VALIDATIONEquipment Loads

• There is just one objective
• TO DEMONSTRATE UNEQUIVOCALLY THAT
• ALL PARTS OF THE LOAD ARE
• SUBJECT TO DRY SATURATED STEAM AT
• THE REQUIRED TEMPERATURE FOR
• THE REQUIRED TIME.

46
Physics versus BIsWhy dry saturated steam?

• ENTHALPY
• Saturated steam at 121 deg. C has an enthalpy of
  2706 joules per gram mass. When it condenses on
  a surface there is a potential transfer of 2198
  joules per gram of condensate produced.
• When the steam condenses the space created is
  replenished with steam.

47
Physics versus BIs

• ENTHALPY
• To put it into perspective to heat a load from
  100 deg. C to 121 deg. C one gram of saturated
  steam has 2287 joules, one gram of saturated
  water has 89.3 joules and dry air has 15.3 joules
  of energy available.
• Reference Thermodynamic properties of steam,
  Keenan Kayes. Encyclopoedia of Pharmaceutical
  Technology, Swarbrick Bolan (Eds)

48
Physics versus BIsCritical Parameters

• Equilibration time, that is , the time for the
  penetration thermocouples to show the same
  temperature as the chamber.
• Equilibration time should be less than 15 seconds
  for chambers less than 800l and 30 seconds for
  larger chambers.

49
Physics versus BIs

• If the equilibration time is exceeded it
  diagnoses
• Inadequate air removal
• OR
• Inadequate steam penetration
• OR
• Excessive non-condensable gases

50
AUTOCLAVE VALIDATION
51
AUTOCLAVE VALIDATION
52
Physics versus BIs

• Leak Rate Test
• Should be performed weekly
• Recommended limit is not more than 1.3 mbar per
  minute

53
Clean Steam Generators

• Feed water not heated to remove non condensable
  gases
• Correct functioning of baffle plates not
  confirmed
• Water droplet removal system (e.g. cyclone) not
  confirmed as functioning
• Lack of venting on generator start up
• or changeover

54
Steam Distribution

• Lack of steam traps
• Lack of air vents
• Steam traps not Near to steam

55
Final Issues

• Deficiencies not rectified site wide and company
  wide
• Same deficiencies found during later inspections
  in different departments different sites
• Specific corrective action taken but no
  preventative action to stop reoccurrence of the
  same deficiency