PHSS I-SIG Technical Confere

INDIA PHSS I-SIG Conference 2014
Welcome & Introduction

India Special Interest Group I-SIG
for Education in GMP
2014 Conference series
James Drinkwater
INDIA Chairman of PHSS – Pharmaceutical & Healthcare
Sciences Society
PHSS F Ziel Head of Aseptic Process Technology &
I-SIG GMP Compliance
1
PHSS I-SIG Conferences
2014 Speaker profile:
Indian Key note Speakers.
Ex-European Regulators/ GMP
inspectors.
PHSS Chairman: Subject matter
expert in Barrier Separation
Technology: Isolators & RABS plus
Vaporised hydrogen peroxide
Gaseous Disinfection.
Director of R&D Filling Technology.
2014 Topics
GMP Compliance in India
Deviation/ OSS Investigation reporting
Control Strategies in GMP
Developments in Aseptic Processing
Developments in Filling Technologies
Facility Design for Aseptic
Manufacturing Plants 2
Processing of Bio-Pharmaceuticals
Open and Closed Aseptic processing
Down stream
Processing
Bio-synthesis - Fermentation
To
Hospital
Pharmacy
3
FRANZ ZIEL GmbH
Pathway to Regulatory (EU/FDA) Compliance
Acceptable Quality & Patient Safety

Good Practice
GLP, GMP, GCP, GPvP, GDP
QMS EU
FDA Q
R QbD
PQS
QRM PAT CPV Metrics
Control
R
Strategy
P M
P Best Practice – risk based M
R
Process Knowledge
Product Knowledge
James Drinkwater FZ Barrier System Technology 4
Control Strategies – Sterile Products
Manufacturing: PHSS White Paper
5
PHSS Bio-contamination Monograph Structure
Chapters 1 Chapters 2 Chapters 3 Chapters 4
Environmental Bio-
Bio-contamination Bio-contamination contamination
monitoring of
Characterisation & Control of classified
Deviation
areas airborne &
profiling management
Surfaces
EM Sample plans
Changing Regulatory Scenario &
expected preparedness of Indian
Pharma Companies
-Rajeev P Patil
Lupin Limited India
PHSS conference at Courtyard Marriot Mumbai November 19, 2014
1
o Is Pharma regulatory environment across the world getting
more tough ?
- Most of us would say yes !
o Why changing regulatory scenario across the globe has to

impact India immensely ?
- It is 10th biggest market
- It contributes $ 15 bn to the world pharma market &
growing at 15%
- It is essentially a generic producer
& world generic market is $ 225 bn & growing at 10% CAGR
- It has aspiration of becoming a main pharma hub.
- R&D, manufacturing, analytical & clinical services are key
aspects of these aspirations.
- It has one of the largest pool of science graduates, doctors,
engineers & pharmacy graduates.
- It has largest number of state-of-the-art API,intermediates
& drug product facilities ( more than 350 facilities
inspected by USFDA, MHRA, WHO, TGA, ANVISA, etc.)
- Its capability is reflected by number of yearly filings &
approval of ANDAs, MAAs, Product Applications & DMFs in
various overseas countries.
- It accounted for 39% of total ANDAs approval in US during
2013 ( 154 ANDAs)
2
o Worldwide regulatory scenario for generics is
changing in multiple ways, becoming complex &
capital intensive.
o New regulatory requirements are brought almost

daily & being global player we need to keep track of
all major markets.
o In India also, the new drug approval process has

become much more stringent and difficult. The laws
surrounding clinical trials have also been tightened.
o -In 2013 only 23 new drugs were approved,

compared to the 140 drugs in 2011.
3
o India being essentially generic producer I will
speak about generics only
o Following are the major areas where regulatory

scenario has changed or is fast changing :
 Product development
 Product approval
 API Development /Outsourcing
 Manufacturing facilities
 Packaging
 BE / CE studies
 Regulatory compliance
 Post approval changes
 Pharmacovigilance, drug safety
4
o Product development
 QbD (Quality by Design)

• It has become buzz word. We cannot carry
out drug development without it.
• USFDA has already implemented it.
Published templates for IR & MR tablets.
• Other regulators have started asking
questions on QbD.
• Europe has brought draft guideline.
5
Product development cont…
Though QbD has put considerable

pressure on resources, it is expected to
help in :-
- Improvement in Product Quality and Product
Robustness/ Reproducibility
- Improved Development Capability, Speed and
Formulation Design
- Increased Process Capability
- Reduced Impact of Raw Material Variability
- Improved Product Stability
- Improved Scale Up Efficiency/Speed
- Reduce regulatory queries.
6
Product development cont…
 USFDA -new guidance for generic development :
• Guidance on size & shape of tables & capsules

• Guidance on score line
• stability studies guidance (+ Q & A) – It is
expected that cost & workload would increase
by 2 fold
• EU – new guidance on BE studies of Modified
Release products is awaited
7
o Product approval
• US FDA introduced GDUFA - on 1st October 2012,

has revolutionized generic drug approval scenario
in US
• It is expected to accelerate approval process
• Industry is suppose to follow certain discipline &
strict compliance with guidance
• FDA brought :-
- Refuse to receive guidance (final September 2014)
- Detailed ANDA & DMF checklist
- EU & Australia regulators – also implemented
time-table based review & approval process.
8
o API Development /Outsourcing
 It has added a new challenge because of increased focus of
regulators.
 ICH Q-11 has become the frame work for API development &
manufacturing.
 Starting material (SM) characterization, source, carryover of

impurities, etc. has gained prominence in review process.
 If SM is too complex, reviewer is asking to redefine it & go few

steps backward
 Reviewers are strictly applying ICH Q 3A & Q3C to limit impurities

based on maximum daily dose
 Limits of genotoxic alerts – TTC approach or based on relevant

studies as per ICH M-7
 Implementation of ICH Q-3D -- Elemental impurities has already

begun.
9
o Manufacturing facilities
 More focus has come on cross contamination
 For highly potent products containment is

expected rather than providing personal
protection equipments.
10
o Expectations about packaging
 Anti counterfeit measures :
• USFDA passed DSCSA in 2013. Effective 1st Jan 2015, the

traceability requirement will apply to transaction of each
product. It covers each manufacturer, re-packager,
wholesale distributor & dispenser.
• Effective Nov 2017, manufacturer has to pass transaction
electronically. Also begin serialization of packs by affixing
product identifier.
• India has also implemented Anti counterfeit measures for
exported secondary & tertiary packs (DGFT directive)
• Many regulated markets have already initiated Serialization
measures (Turkey, etc.) & others are also expected to
bring similar requirements.
 Child resistant packs
11
o BE studies, Clincial end point studies
 Different Approach is taken by different regulators-

Biowaiver for BCS class 1 drugs is not granted by EU ,Brazil
& others but Australia has accepted US FDA’s views.
 For some locally acting oral products , US ask for

In-vitro BE studies, while EU / Australia insist for clinical
end point studies.
 For Ophthalmics – US FDA is giving prior clearance on

Q1/Q2 but other regulators don’t .
 Dose proportionality concept followed by US FDA &

European regulators is different - % of total weight vs.
inactive- active ratio.
12
o Regulatory compliance
 All over world the pharma companies are facing
unprecedented compliances challenges & close regulatory
scrutiny of manufacturing plants, contract analytical labs,
BE & clinical facilities, etc.
 No. of audits by regulators have gone up
 No. of import alerts & warning letters issued by USFDA

has increased in the last two / three years
- USFDA issued import alerts against 21 (49% of all)
Indian manufacturing facilities during 2013
 Majority of the observations were related to practices,

investigations ,CAPAs & data integrity issues.
 In recent months, USFDA has identified more than dozen

Indian companies who have had problems in data
integrity.
13
o Post approval changes
 As global player, we have to comply with variation guidance

of all major regulators – there are distinct differences in
requirements & timeline of approvals .
 TGA revised variation guidance last year
 WHO – Variation guidance amendment in 2013 & 14.
 Beginning Oct 1st , 2014, USFDA has applied GDUFA goals to

electronically submitted PAS .It would reduce approval
time.
14
o Pharmacovigilance, drug safety
 All major regulators have actively implemented

pharmacovigilance & drug safety monitoring measures.
- USFDA has brought out REMS requirement for

many drugs.
- EU has already brought restricted use for drugs like

Trimetazidine, Flupirtine, etc. etc.
15
o Is Indian Industry Prepared for ever changing regulatory scenario ?
 Product development - √
 API development/outsourcing - √
 Manufacturing facilities ,CROs - √
 Packaging –
- Many companies are working to meet Anti counterfeit regulations of most
of the countries.
 BE, clinical end point studies - √
 Regulatory compliance – we need to bring more focus through positive

intervention of top management & by improving- training , discipline,
supervision, quality of investigations, CAPAs, Change controls ,etc.
 We need to be ever prepared for regulatory audits !
 Post- approval changes, Life-cycle management- √
 Pharmacovigilance, drug safety - √
16
Thanks for your attention
-Rajeev P Patil
Lupin Limited India
17
PHSS I-SIG Conference Series 2014
Control Strategy for Contamination and

Cross Contamination Control in
Manufacture of Sterile Medicinal
Products
Di Morris
1
Control Strategy
• Is control strategy something new?
• Like ‘risk’
• It has been integrated into GMP for a long time via
– ICH Q8; Q9; Q10.

– PAT
– Sterility assurance plans
2
Control Strategy
A control strategy is designed to ensure a product of required

quality will be produced consistently
3
Control Strategy
• Q10 control strategy has been integrated into Chapter 1 (31st

January 2013):
1.2 lifecycle stages from the manufacture of investigational

medicinal products, technology transfer, commercial
manufacturing through to product discontinuation
And
1.4 (viii) A state of control is established and maintained
by developing and using effective monitoring and
control systems for process performance and product
quality.
4
Control Strategy
• Annex 2:
• As part of the control strategy, the degree of environmental
control of particulate and microbial contamination of the
production premises should be adapted to the active
substance, intermediate or finished product and the
production step, bearing in mind the potential level of
contamination of the starting materials and the risks to the
product.
• This is a logical scientific approach that can readily form part

of Annex 1.
5
Control Strategy
Hasn’t Chapter 5 always had control measures?:
• Measures to prevent cross-contamination and their

effectiveness should be checked periodically according to set
procedures.
• Processes and procedures should undergo periodic critical

re-validation to ensure that they remain capable of
achieving the intended results.
Note despite what's been written recently Annex 15 never had periodic critical revalidation in it –
it was and still is Chapter 5
6
Control Strategy
• 3 aspects of a control strategy:
1 Manufacturing
2 Quality Control
3 Contamination
For an effective control you have to consider all three

they are totally linked together.
7
Control Strategy - Manufacturing
• Understand the product and processes and write them down

– Document clearly
– Use process mapping
• What are the critical process parameters

– For the starting materials
– For the product
– For the process
– For the facility
8
Control Strategy
• For sterile products the issues are
 they have to be manufactured consistently

But also
 Be sterile
 Or have a controlled bio-burden
• Therefore contamination/cross contamination control is

essential.
9
Control Strategy – Contamination controls
Things to consider to prevent contamination/cross

contamination:
• The complete process - the basis of the manufacturing
controls
• Map out the products manufacturing steps
– From each component and starting material used
– The handling and flow of those materials and people
– The environmental controls that are in place - limits applied to
materials, equipment, facility
– The classification and control for each area
– The equipment used, handled, cleaned, decontaminated
– Determine the risk areas and document their mitigation
10
Control Strategy
• Continue into filling/lyophilisation

– What are the filling controls
• RABS (open/closed) vs isolators vs traditional design
• Single filtration vs point of fill filtration
– Aseptic fill vs terminally sterilised
– Facility zoning, HVAC controls – pressure differentials, temperature &
humidity
– Sterility assurance plans
– Microbiological aspects - know your limits for classified and controlled
areas, contamination risk areas and the response to those risks
– Container closure and how to demonstrate they are integral
11
Control Strategy – contamination control
 Environmental controls
- To ensure sterility assurance
- Patient safety
are not compromised
- loss of microbial control

- loss of the controlled environments
Does your monitoring system detect quickly enough if you are

deviating away from your critical control parameter
12
Control Strategy
• by developing and using effective monitoring

• How do you demonstrate that your strategy is working and is
being verified?
– It has to form part of your validation master plan
– the control strategy should be integrated into the Process Qualification
and re-qualification activities of the critical process (Chapter 5
requirements)
– Critical includes sterilisation, disinfection, environmental controls,
utilities, media simulations etc
– Do your procedures still work, they should be evaluated at the same
time
– Any changes that could impact any of the above
13
Control Strategy
• People (the biggest risk to a sterile product)

– Numbers allowed in the area
– How they get in
– How are they qualified
– What are the gowning requirements, how are they monitored
– Are the critical aseptic manipulations clear and understood
– What are the corrective and preventive measures to assure there is no
breach to control or sterility assurance
14
Control Strategy – Microbial Control
• Know your risks

– Understand the zoning of your classified areas
– Understand the risks posed by transfer of materials and people from
controlled/unclassified areas.
– What are your bio-burden controls, are the limits appropriate
– What are your ‘typical’ micro-flora knowing there should be none in
Grade A and significantly less in Grade B and what are those in the less
classified areas
– Can your monitoring detect break-through and would you know what
they were?
– What are the cleaning and disinfection/sanitisation controls and have
they been verified against your facility isolates
15
Control Strategy – Microbial Control
• Know your cross contamination risks

– Define them for your process
– Consider whether they are chemical, biological, or for some products
patient biological entities (cells etc)
– In this consideration microbiological cross contamination is the
process driven contamination ie fermentation open/closed systems
and transfers that require controls
– Should containment and product segregation principles be used
16
Control Strategy – Risk Management
 Use Risk Management Principles

 They have to be sound and scientific
 As you process map document:
 The identification of sources of contamination and routes of transfer
 Assess the risks of those sources and routes
 Establish monitoring schedules and appropriate limits
 Verify they still work
 Maintain appropriate documentation
 Maintain a rigorous training programme of personnel and not just routine
clean-room staff
 Determine the microbial risk to the patient from the product
17
Control Strategy
• Control Strategy is
– Common sense
• Know your product
• Your facility
• Where possible use closed systems
• Define your mitigation strategy for any risk areas
• How you transfer people, material, products around and through your
critical areas
• Monitor your data
• Act upon your data
• Include all outcomes as part of the validation strategy
• Discuss at the Management Review
• Document and update your strategy with any new learnings or
approaches being undertaken – it is a ‘live’ document
18
Control Strategy
Thank you
Di Morris
di@qpservice.co.uk
07775 763270
www.pharmaceuticalsolutions.co.uk
19
Is Indian industry over designing the
Aseptic Manufacturing Plants it builds ?
Is it possible to over play Aseptic operations ?
Dr Jean-Denis Mallet
GMP Expert, Pharmacist
PHSS India ISIG 2014 Conference series ; Mumbai & Goa, November 2014
PHSS Presentation 2: 11:15 am – 12:15 pm
Is Indian industry over designing

the Aseptic Manufacturing Plants it builds ?
NNE Pharmaplan Consultant
formerly Head
of the French GMP Inspections
2 PHSS Conferences, Mumbai, 20 Nov. 2014 & Goa, 22 Nov. 2014

Senior Technology Partner, NNE PHARMAPLAN
GMP Compliance Manager SNC Lavalin Pharma
International Auditor, CICR (The Red Cross)
GMP Consultant, (NNE) Pharmaplan
Head of the GMP inspection, the French Agency
GMP Consultant, Pharmaplan
Quality Assurance Director, Ipsen
Quality General Manager, Janssen-Cilag (J&J)
GMP inspector, the French Agency
Production Manager, Pharmygiene (Omega)
Dr J-D Mallet
Quality Assurance Manager, Janssen (J&J)
Jdma@nnepharmaplan.com Technical Assistant, Roussel-Diamant Maroc
Pharmacist, MBA

I performed about 500 inspections or audits since 1994
of which some 42 were in India of which 17 in sterile facilities

Agenda
Brief history of the development of sterile GMP guidances

(from 1963 to 2014)
Current guidances : America, Europe, Japan and India

(a comparison)
Changes brought by the 2008 European Annex 1

(bioburden monitoring, media-fill tests, vial capping)
Recent trends in regulatory expectations

(some FDA findings)
An ideal design for an ideal aseptic facility ?

Agenda

(from 1963 to 2014)

(a comparison)


(some FDA findings)

1963 : the very first cGMP issued in the USA few words
1969 : the WHO GMPs are published few paragraphs

1971 : revision of the (FDA’s) cGMP 21CFR210-211
1971 : first publication of the Orange guide* (UK) first real annex for steriles
1975 : revision of the WHO GMP guide
1976 : 21CFR212 draft for parenteral products never published in the FR
1978 : second revision of the 21CFR210-211 (current)

1987 : first FDA aseptic processing guidance first aseptic guidance
1989 : PIC/S* & EU-GMP guide first published contains annex 1 for steriles
1994 : FDA guide to inspection of sterile APIs
1996 : first revision of the EU-GMP annex 1
2002 : first Indian GMP published in the Gazette contains an annex for steriles
2004 : revised FDA aseptic processing guidance a very detailed document (50p)
2006 : Japanese guidance on aseptic processing a 100+ page document
2008 : last revision of the EU-GMP annex 1 under revision again ?

The first cGMP regulations were issued by Geo. P. Larrick,
Commissioner of Food and Drugs (FDA) one year after the
Kefauver enactment, on June 20, 1963, in the Federal Register
Pyrogen free
sterile
products
premises
8 columns in the FR

The first WHO cGMP guide (an 8 page document) has been
adopted by the 22nd World Assembly in December 1969
few paragraphs (6)
terminal
sterilization
aseptic
processing
monitoring
4.2

few paragraphs (con’t)
equipment
checks
premises
layout
laminar
air-flow
techniques

1971
a 10-page document not requiring MFT (revised in 1974)
1975
a general WHO document mentioning the MFT for validation
1976 a very specialized document addressing the

manufacturing conditions for terminally sterilized SVPs
and LVPs – it has never been published as a guide
1978 a general document that has been

amended at several occasions but which
is still the compendial FDA cGMP guide
1987 FDA guide (40 pages)

on sterile products
produced by aseptic
processing – containing
new detailed requirements
which underlined the
concept of critical areas

1989 Annex 1 to the EU-GMP similar to the
Annex 1 to the PH 5/89 guide of PIC/S which
itself has been inspired from the Orange guide
successive annexes (1971, 1974,1977 & 1983)
1996 A major revision of the Annex 1 to the EU-GMP

introducing the concept of grade A continuity
2001 Revision of two points (MFT and gowning)
2003 Revision of the 5µ particle counts
in the classification table (one, not zero)
2008 This revised version of the
Annex 1 for sterile products has
been re-arranged and includes
four important changes :
- 5µ particle counts revised
- new provisions for MFT
- precisions on bioburden
- increased environmental
requirements for capping seals
This annex has now 15 pages of
requirements (few explanations
are given on the contrary of
some other Int’l guidances

Agenda

(from 1963 to 2014)

(a comparison)


(some FDA findings)

2002 2004
16 pages 50 pages
Sterilized Aseptic
Aseptic
2008 2011
15 pages 110 pages
Sterilized Aseptic
Aseptic

Table 1 : comparison of environment classification
2002 2004 2008 2011

INDIA USA EUROPE JAPAN
16 pages 50 pages 15 pages 110 pages
Terminal & Aseptic Aseptic Terminal & Aseptic Aseptic

4 grades 4 grades 4 grades 4 grades
A, B, C & D ISO 5, 6, 7 & 8 A, B, C & D A(5), B(7), C(8) & D
0,5 µ particles 0,5 µ particles 0,5 µ particles 0,5 µ particles
5,0 µ particles --- 5,0 µ particles 5,0 µ particles
At Rest & In Op. In Operation At Rest & In Op. At Rest & In Op.
Class A in Op. is : ISO 5 in operation Class A in Op. is : Class A in Op. is :

3500 (0,5) / 0 (5) 3520 (0,5) 3520 (0,5) / 20 (5) 3520 (0,5) / 20 (5)

< 1cfu/m3) 1cfu/m3 < 1cfu/m3 < 1cfu/m3
It should be noted here that the revised schedule M states for 29 particles in A but 293 in B

Table 2 : comparison of microbiological grades
2002 2004 2008 2011

Air sampling Air sampling Air sampling Air sampling
Settle plates Settle plates (opt.) Settle plates Settle plates
--- --- Surfaces Surfaces
Fingers Fingers Fingers Fingers
A <1 cfu/m3 ISO 5 1 cfu/m3 A <1 cfu/m3 A <1 cfu/m3
B 10 cfu/m3 ISO 6 7 cfu/m3 B 10 cfu/m3 B 10 cfu/m3
C 100 cfu/m3 ISO 7 10 cfu/m3 C 100 cfu/m3 C 100 cfu/m3
D 500 cfu/m3 ISO 8 100 cfu/m3 D 200 cfu/m3 D 200 cfu/m3
A <1 / plate ISO 5 1 / plate A <1 / plate A <1 / plate
B 5 / plate ISO 6 3 / plate B 5 / plate B 5 / plate
C 50 / plate ISO 7 5 / plate C 50 / plate C 50 / plate
D 100 / plate ISO 8 50 / plate D 100 / plate D 100 / plate
Pl. Time exposure Plate time exposure Plate tilme exposure Plate time exposure
minimum 2 hours 4 hours 4 hours 4 hours
and 30 minutes in A

Table 3 : comparison of engineering basics

Manufacturing Separate rooms
“Direct support
and support depending on
Clearly stated Clearly stated area“ and “indirect
areas separation operations but
support area“
not so explicit
Smooth internal Rounded floor
surfaces and Non explicit for Non explicit for the
Clearly stated & accessible
coves the coving coving
corners
Airlocks and Final stage of

Black Focus on the
changing rooms the same grade Separate rooms
Grey entry/exit
(at rest) that the for entry and exit
White process
final area
Drains Prohibited in Prohibited in Prohibited in A/B
Only in ISO 8
Class A & B Class A & B Conditions for C
Aseptic handling
A in B ISO 5 in 6 or 7 A in B A in B
conditions

Table 4 : comparison of HVAC basics
Clean up time 30 minutes not specified 15-20 minutes 15-20 minutes
Not specified Minimum 30 in

Air Change Per Minimum 20 for Typically 20 for
(was 20 in old Grade B and
Hour Grade B and C Class ISO 8
versions) minimum 20 in C
Air velocity in 0,45 m/s (hor.)

0,45 m/s 0,45 m/s 0,45 m/s
laminar airflows 0,30 m/s (ver.)
Delta-P 10-15 Pa
At least At least
between two 15 Pa at least (guidance
10-15 Pa 10 to 15 Pa
classes (pascals) value)
HEPA integrity Twice a year At least once a

Yearly Not specified
testing (DOP) (for aseptic) year

Table 5 : comparison of basics instructions
Sterilized
At each work At each work Should not be
garments Gown change
session session reused
(aseptic)
Sterilized or
Sanitized Sterilized
Goggles Not mentioned desinfected
goggles goggles
goggles
Product filter Optional before

Immediately Before and after
integrity routinely after Not specified
after use use
verification use
Supervision of Intercom From outside the Windows or

Not explicit
operations telephones clean area video cameras
Temperature Should not Should be

Temperature < 27°C
and humidity interfere with the compatible
and humidity <55% RH
controls standard and controlle

Figure 1 : situation resulting from a poor engineering
Free cables*
Shedding
elbow
Door open*
Agenda

(from 1963 to 2014)

(a comparison)


(some FDA findings)

EUROPEAN GMP Guideline Story (annex 1)
Orange Guide, 1971 (the ancestor – 4 pages)
Orange Guide, 1974 (first revision – 8 pages)
Orange Guide, 1977 (second revision – 9 pages)
Orange Guide, 1983 (third revision – 15 pages)
EU-GMP Guide, 1992 (initial release ; no % for MFT)
EU-GMP Guide, 1996 (first revision ; MFT 0,1%)
EU-GMP Guide, 2001 (revision § 42 ; MFT twice a year)
EU-GMP Guide, 2003 (2nd revision ; one five µ particule in A)
EU-GMP Guide, 2008 (current version ; MFT target zero growth)

Validation of the aseptic filling : media fill test (Ed.1992 : 29 words)
Aseptic processes or significant

modifications should be validated by using
a sterile nutrient medium for simulating
the process to be performed. That
validation should be repeated at defined
intervals (Annex 1, § 38).

Validation of aseptic processing should include simulating the process

using a nutrient medium. The form of the nutrient medium used should
generally be equivalent to the dosage form of the product. The process
simulation test should imitate, as closely as possible the routine aseptic
manufacturing process and include all the critical subsequent
manufacturing steps. Process simulation should be repeated at defined
intervals and after any significant modification to the equipment and
process. The number of containers used for a medium fill should be
sufficient to enable a valid evaluation. For small batches, the number of
containers for the medium fill should at least equal the size of the
product batch. The contamination rate should be less than 0.1% with
95% confidence level (Annex 1, § 42).

Validation of aseptic processing should include a process simulation test using a

nutrient medium (media fill). Selection of the nutrient medium should be made based
on dosage form of the product and selectivity, clarity, concentration and suitability for
sterilisation of the nutrient medium. The process simulation test should imitate as
closely as possible the routine aseptic manufacturing process and include all the
citical subsequent manufacturing steps. It should also take into account various
interventions known to occur during normal production as well as worst case
situations. Process simulation tests should be performed as initial validation with three
consecutive satisfactory simulation tests per shift and repeated at defined intervals
and after any significant modification to the HVAC-system, equipment, process and
number of shifts. Normally process simulation tests should be repeated twice a year
per shift and process. The number of containers used for media fills should be
sufficient to enable a valid evaluation. For small batches, the number of containers for
media fills should at least equal the size of the product batch. The target should be
zero growth but a contamination rate of less than 0.1% with 95% confidence limit is
acceptable. The manufacturer should establish alert and action limits. Any
contamination should be investigated (Annex 1, § 42).

Validation of aseptic processing should include a process simulation test using a nutrient medium (media
fill). Selection of the nutrient medium should be made based on dosage form of the product and selectivity,
clarity, concentration and suitability for sterilisation of the nutrient medium.
The process simulation test should imitate as closely as possible the routine aseptic manufacturing process
and include all the critical subsequent manufacturing steps. It should also take into account various
interventions known to occur during normal production as well as worst-case situations.
Process simulation tests should be performed as initial validation with three consecutive satisfactory
simulation tests per shift and repeated at defined intervals and after any significant modification to the
HVAC-system, equipment, process and number of shifts. Normally process simulation tests should be
repeated twice a year per shift and process.
The number of containers used for media fills should be sufficient to enable a valid evaluation. For small
batches, the number of containers for media fills should at least equal the size of the product batch. The
target should be zero growth and the following should apply:
When filling fewer than 5000 units, no contaminated units should be detected. When filling 5,000 to 10,000
units : One contaminated unit should result in an investigation, including consideration of a repeat
media fill ; Two contaminated units are considered cause for revalidation, following investigation.
When filling more than 10,000 units : One contaminated unit should result in an investigation;
Two contaminated units are considered cause for revalidation, following investigation.
For any run size, intermittent incidents of microbial contamination may be indicative of low-level
contamination that should be investigated. Investigation of gross failures should include the potential impact
on the sterility assurance of batches manufactured since the last successful media fill (Annex 1, § 66-70).

Annex 1 : from 1992 to 2008 (sixteen years of improvements)
289
Number
of words
contained 6800
in annex 1 205 205
+50% 6100
122 5800
5700
10 folds
4600
49
the
Annex 1 number
of words
29
for MFT
1992 1996 2001 2003 2008

EU-GMP
Annex 1
eudralex vol.4
(Dec.2009
published
Completed with
Feb.2008
PIC/S PI032-1 )
re-published
Nov.2008 INTERPRETATION OF
MOST IMPORTANT
coming into force CHANGES FOR THE
in March 2009 MANUFACTURE OF
STERILE MEDICINAL
and March 2010*
PRODUCTS
+ PIC/S PI032-2
(January 2010)

EU-GMP
Annex 1 story

EU-GMP
Annex 1 story
And now ?

EUROPEAN GMP Guideline Story : it continues !
What has to be
discussed now is
“how big” is the
updating need :
a) clarification
Grade A air supplies
b) revision
e.g. new technologies
c) re-writing
e.g. missing forms
d) harmonization

Agenda

(from 1963 to 2014)

(a comparison)


(some FDA findings)

While the EMA has started now to post non-compliance reports
on its eudragmp website, the US-FDA website is by far the
place where you can get the richest information :

Most of the failings identified by the FDA or the European
inspectors are related with poor or even bad practices that are
not directly linked with the premises or the equipment :
Your firm has not established or followed the appropriate written

procedures designed to prevent microbiological contamination of
drug products purporting to be sterile. For example, approximately
846 environmental monitoring (EM) samples were not collected
in the Class 100 (Grade A) and the Class 10,000 (Grade C) areas
from March 2010 to February 2012 during the manufacture of
sterile injectable products … [320-13-03]
Operators working inside the aseptic core were observed wearing

goggles that had not been adequately sterilized and had two
openings on the top. The goggles currently worn in the Class 100
area are not sterilized but rather sanitized …. [320-13-03]

US-FDA failings (continued)
Your firm failed to establish an adequate system for monitoring

environmental conditions in aseptic processing areas in that the
inspectors found that you do not have a scientific justification for
alternating the use of sampling by settle plates and swabs
and we are concerned that you may have underestimated the
number and type of bacterial species that are present on the
two different geloses you use because you have no data to
support the equivalent sensitivity and efficiency of bacterial
recovery on these supports … [320-14-15]
We note that your firm prepares the media plates used for EM
sampling at your site. Prior to using them, you pre-incubate the
plates and we are concerned that this practice may compromise the
media’s growth promotion potential. Provide evidence to demonstrate
that pre-incubation of the media plates does not adversely impact the
ability to promote microbial growth… [320-15-003]

You have have not performed smoke studies under dynamic

conditions to ensure that unidirectional airflow protects the
product during aseptic filling operations. In your response, you
indicate that you are making arrangements to perform dynamic
smoke studies. However, your response fails to provide any
justification that the aseptic processing line has proper airflow
Our investigators observed poor aseptic practices that increase
the risk to product sterility assurance. For example, operators
with exposed skin were observed making interventions over
open product using a non-sterile forceps.
Our investigators observed inadequate gowning of operators
who routinely reused gowning throughout the day to enter
the sterile core for set-up and filling… [320-14-07]

Your firm failed to maintain the buildings used in the

manufacture, processing, packing, or holding of a drug product
in a clean and sanitary condition and keep them free of
infestation by rodents, birds, insects, and other vermin :
a. during the inspection of the facilities, investigators noted
significant mold growth in the washroom located at the entry to
the sterile manufacturing area […]
b. the investigators noted numerous dead insects in the
“Sample Pass Through” Room, located approximately […] from
the small volume parenterals sterile filling line… [320-14-13]

Table 6 : inspection findings and engineering
Engineering
WL Finding Correction
impact (ex.)
EM sampling missed Ancillary area

320-13-03
Non sterilized goggle Table top sterilizer
Two different methods in Ancillary area

320-14-15 alternance – 2 geloses Laboratory
Pre-incubation of the
320-15-03 Probably no impact
environmental plates
No smoke studies
Line refurbishing
320-14-07 Exposed skin
Airlock refreshing
Gowning reused
Mold growth HVAC refreshing

320-14-13
Dead insects Additional rooms

Remember !
3 5

Agenda

(from 1963 to 2014)

(a comparison)


(some FDA findings)

Figure 2 : an ideal facility ?

Figure 3 : continuous improvement is a must
Milieu
Methods
Men
Materials
Machines
EU-GMP 1996 revision

What is needed in an ideal facility ?
A full knowledge and understanding of the process
PAL storage
MAL
X
personnel rooms
material post
airlock(s)
airlock(s) processing
rooms
washing
IPC Core room
Core room
room(s)
rooms
sterilization
preparation
room(s)
room(s)

A good definition of the ventilation needs
Grade Air
Which operation(s)
(Class) Changes
A Critical +600
& use of systems
B No operation 60 where necessary
X
C Non critical 30
D Preparation 20
E No operation 12
(CNC)
F Circulation 6
This table only reflects the personal opinion of the author on the topic

A full control of entries and exits
ingress
filtered AIR C personnel

F H
personnel I E products
C
materials L K waste
T Core room -
V
fluids & gases
E A
equipment
L
consumables R V (drains)
S E
equipment S extracted AIR
leaks

A perfect control* of all exposed surfaces
X
lights
doors
walls windows
pipes
covings equipment
grids
floors
* Controlled means : cleanable, smooth, inert, resistant, non electrostatic, etc.

A plain layout with successive clean areas
E/B B/C C/D
COMPONENT FILLING (A) PACKAGING (D)

HANDLING (B)
D/B
PACKAGING MAT.
PREPARATION (D)
NON CRITICAL OPERATIONS (C)
E/D E/D E/C C/D D/E E/D E/D
CORRIDOR (E)

What is the cost of an ideal facility ?
Costs of design flaw(s) :
depending on the time
where such failure(s)
Is(are) identified … 1 if identified during consultancy
10 if identified during conceptual
100 if identified during basics
if identified
1000 during detailed
maybe 100 crores if identified by inspectors

Thank you very much
Jean-Denis Mallet
Any
Docteurquestion
en pharmacie ?
Diplômé de la Faculté de Tours
Is it possible to over play aseptic operations ?

to me, the answer is clearly “no you can’t”
PHSS Conferences, Mumbai, 20 Nov. 2014 & Goa, 22 Nov. 2014

Please remember…
when processing aseptically,

the devil is in the details

Thank you all again
Jean-Denis Mallet
for inviting me in Goa
Docteur en pharmacie
NNE PHARMAPLAN
INDIA PHSS I-SIG Conference 2014

Bio-Contamination Control
&
Cross Contamination Control
James Drinkwater
INDIA Chairman of PHSS – Pharmaceutical & Healthcare
Sciences Society
PHSS F Ziel Head of Aseptic Process Technology &
I-SIG GMP Compliance
1
Bio-contamination Control
in Aseptic processing
• Contamination control principles and attributes of controlled areas:
Airflow, pressure regimes, Material transfer control points (Hatches with
disinfection steps), Personnel transfer control points (gowning and change
rooms).
• Control Strategies for Sterile product manufacture (terminally sterilized
and Aseptically processed products).
• Sanitization and Disinfection programs (qualification and regimes).
Including Bio-decontamination hierarchy: Sterilization> Gaseous
Disinfection Surface Sterilization> area/ surfaces Automated Gaseous
Disinfection, Semi Automated Aerosol area/ surfaces disinfection> Manual
Sanitization/ Disinfection process and Manual Sanitization/ Disinfection
procedures.
• Progression through process of establishing control (implementing
disinfection regimes and control measures) to formal state of control with
monitoring to confirm control measures are effective.
2
FRANZ ZIEL GmbH
New GMP Initiatives: Bio-contamination Control &

• EU Annex 1 revision in Monitoring:
progress. • Holistic trending of EM data
• Control strategies for • Implemented Rapid and Real
manufacturing Sterile Time viable monitoring
products: a new requirement. methods (RMM, RTM)
• FDA Quality metrics • Improved bio-contamination
• RPPR (Risk profiling and control in material transfers:
proactive response) Developments VHP Rapid decon for material
• Graphical SOPs to reduce transfer replacing manual
human errors
in disinfection of packaged items
Aseptic
Processing Process improvements:
Aseptic processing technology
• Increase in Small Batch/ Technologies • Improved flexibility and
flexible filling for biologicals. and GMP modularity in Filling systems
More Single use systems • More integrated systems &
• Pre-sterilised containers
initiatives process control
using De-bagger No touch • Shorter VHP cycles, reduced
transfer technology. Increase production downtime.
in Rapid Material Decon • Surface sterilization: Gassing-
transfers using VHP in-place accepted in GMP
• More closed systems for • More automation less human
Biotech factors
OZI - V1.1 Technical Presentation 3

Key Issues in Bio-contamination Control
Photographs courtesy of F Ziel GmbH.
• Gowned operators generate microorganisms so following Quality by Design principles a physical separation barrier
between the process/ product and the most contaminating source ‘people’ e.g. with Isolators, RABS is required
particularly in Aseptic processing that is increasing with new biological products.
• Environmental monitoring is limited in recovery with limited sample sizes and sample areas/ volumes meaning we
only have an indication not absolute values on contamination levels; trends (much data) are needed to indicate state
of control. A single measuring event has little value on its own.
• We are still learning about disinfection and developing new approaches: Manual, Semi-automatic and Automatic.
Isolators are typically decontaminated with vH2O2 – VHP (bench mark), other automated gaseous disinfection
processes may apply, and still there is not widespread knowledge in this area: An understanding of Science, Process
and Microbiology are key to efficacy, efficiency and GMP compliance.
• Despite being an established process the industry still has problems with Moist heat sterilisation.
4
Processing of Bio-Pharmaceuticals
& Aseptic processing
Down stream
Processing
Bio-synthesis - Fermentation
To
Hospital
Transition through ‘Closed to Open’ Aseptic Processing
Pharmacie
s
Progress through Establishing control to

formal state of control
Holistic EM ‘profile’ monitoring and proactive

responses to Bio-contamination risk escalation
5
cGMP/ GMP Pathway : Aseptic processing
cGMP Compliance matrix 6

James Drinkwater
GMP and Best Practice Guidance
European Pharmacopoeia (EP) 3rd edition.
United States Pharmacopoeia (USP): 2005.
Japanese Pharmacopoeia (JP).
EU GMP Annex 1. Manufacture of Sterile Medicinal products – ‘Orange Guide’

FDA – Guide to Industry, Sterile drug products produced by Aseptic processing
– Current Good Manufacturing Practice. Sept 2004.
Pharmaceutical
Isolators
PDA Guides ISPE
&
Pharmacy Quality
TR’S Guides
Assurance RABS Bio-
contamination Technical Risk
‘Yellow guides’ Guide
Guide Reports Maps
<USP797> New for 2014 <USP1116>

FRANZ ZIEL GmbH
Pathway to Regulatory (EU/FDA) Compliance
Acceptable Quality & Patient Safety

Good Practice
GLP, GMP, GCP, GPvP, GDP
QMS EU
FDA Q
R QbD
PQS
QRM PAT CPV Metrics
Control
R
Strategy
P M
P Best Practice – risk based
M
Technical and organisational measures
R
Process Knowledge
Product Knowledge
James Drinkwater FZ Barrier System Technology 8
Control Strategies – Sterile Products
Manufacturing: PHSS White Paper
9
Control Strategies
• A Control Strategy should be considered to include: All are

inextricably linked.
• Manufacturing control strategy; based on product type,
demand, process and risk.
• Quality control strategy; based on understanding of risk with
control of Critical Quality Attributes (CQAs) in a manufacturing
process meeting regulatory requirements.
• Contamination control strategy including cross contamination
control that may include requirements for containment/ product
segregation.
• The PDA are developing guidance on Control strategies for
ATMPs.
3
Process Equipment GMP Compliance Matrix
For Filling system and Barrier Isolator
Establishing Environmental / Contamination control Formal State of Control
FQT T
Cleanroom Qualification
Module A Module B R
interfacing
Product manufacturing
Type Test Qual Type Test Qual
TTQ TTQ
A Media
I
FQT A FQT B N Fills
I
FAT – process system N
G
Process
IQ Process System
: Simulations
S Process
OQ Process System O Validation
OQ GD-VHP & EM system –SAT P
PQ Process system ( Filler & Isolator) s
PQ GD-VHP & EM (Environmental control) Other Qualification
streams 11
PHSS Bio-contamination Monograph Structure
Chapters 1 Chapters 2 Chapters 3 Chapters 4
Environmental Bio-
Bio-contamination Bio-contamination contamination
monitoring of
Characterisation & Control of classified
Deviation
areas airborne &
profiling management
Surfaces
EM Sample plans
Bio-contamination definitions
• Bio-burden in a controlled area is microbiological flora, airborne

or on surfaces, pre and post cleaning/ disinfection/ sanitization
step. Depending on the manufacturing stage bio-burden may
not be fully characterised; not differentiated as microbiological
isolates or micro-flora.
• Micro-flora is characterised as ‘‘typical flora’ being the typical
microbiological flora found in a controlled area under controlled
conditions.
There should be no typical flora in Grade A controlled areas and significantly
limited flora in Grade B areas. Characterisation includes identification of
microorganisms by groups or isolates (as required) including genus, species or
sub-specifies (as required) and includes whether organisms are objectionable to
products and potentially harmful to patients.
Note: ISO14698 also references the term; micro-flora.
3
Bio-contamination definitions
• Bio-contamination is defined as microbiological contamination

above set levels/ limits: alert levels (user set) and action levels
(from regulatory guidance) together with determination as
atypical micro-flora.
Bio-contamination may also be detected as an adverse trend
where levels of cfu counts increase above typical levels
indicating and change in control conditions that may not yet
have reached action levels.
• Bio-contamination is a combination of all biological

contamination, including viruses, and related components. Bio-
contamination includes microbiological contamination,
endotoxins and pyrogens.
3
Resident and Transient microflora in
Controlled Environments
Microflora on
Materials in
transfer Microflora
Microflora on transfer from
Hand transfer Surrounding
Environment
Isolator
Controlled Zones
15
Zonation of classified areas
RABS
Unclassified Areas / zones
EU Grade D : at Rest ISO8: In Operation
EU Grade C
ISO8 in operation
in operation
EU Grade B ISO7
in operation in operation
Aseptic core
EU Grade A
Cleanrooms ISO 5 Isolators
in operat ion
EU Grade C ISO7 in operation

at Rest Air Flow &
Pressure
Cascade
* PCCA
*BFS
3
Classified Area Zonation
Unclassif ied Areas / z ones / PCCA*
EU Grade C
ISO8 in operation
in operation
EU Grade B ISO7
Aseptic core
EU Grade A
ISO 5
in operat ion

at Rest
Conventional Cleanrooms without Operator Separation Barrier Systems

3
Control Targets: Total particulate & Microbiological levels
GMP Annex 1 > ISO 14644 Parts 1 & 2
Total Particles 3520000 (0.5 µ ) <In Operation>
Viable & 29000 (5 µ) 3520000 (0.5 µ ) 352000 (0.5 µ ) 3520 (0.5 micron)
Non viable > at Rest. 29000 (5 µ) 2900 (5 µ) 20 (5 micron)
EU : D C : ISO8 B : ISO 7 A Controlled
Personal & 100 50 5 ISO5 Direct input
Material 50 25 5 <1cfu =
Utilities /
3/6 log
Transfers 0 cfu services e.g.
n/a 3 log n/a 3log 5
3 log WFI & HVAC
200 cfu 100 cfu 10 cfu
Microbiological •Settle plates max cfu. <In Operation>

Contamination as ISO 14698
•Contact plates max cfu.
colony forming units >
(cfu) •Glove prints max cfu. FDA guidance.
•Active air cfu / cubic metre.
USP<797> & <1116>
Air flow & Pressure Cascade direction

To prevent the entry of air from a less clean adjacent area, the air pressure
within the controlled area is maintained at a higher pressure. Differential
pressures of 10 Pa between classified areas and 15 Pa between a classified
and an unclassified area are reasonable minimum values to ensure that the
air moves outwards from the areas of highest cleanliness.
EnvironmentalCombination monitoring
Monitoring Systems – Data methods
Trending
integrated for Holistic interpretation
D50
19
Environmental monitoring programs must be set for
Media fills and process simulations and routine use.
Monitoring results trending

starts from PQ, into Media
fills and routine operation.
Trends are required to set
Action and Alert levels and
monitoring system alarm
responses.
Risk based Sample Locations
Value of sampling location?
HEPA filter delivering ‘First Air’
Air disturbance – potential

contaminating source.
I M3
Columns
of ‘First’
clean air
Point Settle
of Fill Plate
21
EM – Monitoring combinations
Combination provide
monitoring in aIsolators
picture
End of session contact plates on

Stopper bowl surfaces monitoring
HEPA Filter ‘depositing micro flora.
Settle plates – positioned by smoke

study, monitor Microbe carrying particles
from the stopper bowl.
‘First Air’ The ISO Kinetic cone for total particle
End of
counting monitors for air quality or
session disturbance that may include micro flora
Finger
Dabs
at point of fill.
Active air samples qualify the Grade A

air micro flora condition in critical
locations.
Stopper
Bowl
Active air End of session Finger dabs monitor for
sampler
‘worst case’ contamination on Gloves
Contact
Plate Settle Total that may have transferred to critical
Plate particulate surfaces of product.
In QbD Open vials and product should only be in contact with ‘first air’.
In best practice Barrier gloves should not pass over or contact critical surfaces.
22
EM - Monitoring Current challenges and
Monitoring Key issues under review
Developments
• What incubation regime to select: EM incubation regimes: selected
single temp. Dual Temp one plate. Dual temp two TSA plates or
TSA/SDA.
• Classical EM and EM with RMM Real Time monitoring technology:
Managing the data – CFU vs Bio Count.
• The ‘5.0 micron particle issue’: linkage with Bio-contamination?
• The USP<1116> ‘15 CFU incidence’ issue?
• Implementation of intervention free RMM monitoring technologies
to reduce risk of bio-contamination in sampling – why so little
uptake?
• Real time deviation response and how to manage?
• Investigations into trend deviations how are they reported and acted
on?
EM - Monitoring and Incubation regimes
Dual Temperatures two EM sample incubation Good for setting baselines,

plates (TSA + SAB): qualification + investigations/
TSA plate 30-35 0C – 3 days adverse trends.
SDA plate 20-25 0C – 5 days Used in Sterility testing.
30-35 0C – 3 days (Bacteria + Increased evidence that with
Dual temperature on one Human commensals) temperature change on same
TSA plate. plate there is a loss of recovery.
20-25 0C – 5 days
(Fungi, moulds)
Selected temps/ Plates: In Qualification two plates: Dual plates and temperatures
Combination temperatures TSA: 30-35 0C – 3 days during investigations and
A) Dual Temps two plates. SDA: 20-25 0C – 5 days periodic reviews.
B) Selected Temps on TSA. In monitoring one TSA: Plus Monitor A/B/C transfer interfaces
Research in progress to verify broad periodic two temperatures. TSA: 20-25 0C
spectrum recovery in Cleanrooms at A/B zones 30-35 0C –3 days
20-25 0C on TSA C/D zones 20-25 0C –5 days
Anaerobic 30-35 0C – minimum 5 days Different monitoring strategies
depending on risk. Minimum in
setting baselines/ qualification.
USP<1116> Incidence Rates
The latest revision (current at 2014) of USP General Information Chapter <1116>
Microbiological Control and Monitoring of Aseptic Processing Environments now applies
percentage contamination recovery rates instead of the standard use of maximum
permissible limits or levels for microbiological monitoring. Please refer to Table 4.3 below.
This departure from convention has been written with good intentions recognising that the
real value of environmental monitoring programmes lies in their ability to detect changes in
contamination rates which may be indicative of changes in the environmental state of
control.
To accept infrequent but persistent recoveries which fall within the specified acceptable
contamination rates, as recommended in USP<1116> chapter, without investigation, would
be an acceptance of poor aseptic control. In addition the USP chapter states that only
excursions which exceed 15 CFUs on single ISO 5 samples, which albeit should occur very
infrequently, may actually be indicative of a significant loss of control. The inference here
being that pharmaceutical and bio-pharmaceutical manufacturers and others involved in
aseptic processing or healthcare product aseptic compounding should be prepared to accept
occasional counts up to 15 CFUs, providing that the specified incident rates are not
exceeded.
The document does require however that single counts above 15 CFUs, should be
correlated against other lower level recoveries if present within at least a two week period.
The USP approach has not been endorsed by the EU or US authorities at the time of
publication. 3
Contamination or Incidence Rates
Table 4.3. from USP<1116> Chapter:

Suggested Initial Contamination Recovery Rates in Aseptic Environments a
Active air Settle Plate Contact Glove or

sample (9cm) 4hr Plate or Garment
Room Classification
Exposure (%) Swab (%) (%)
(%)
Isolator/Closed RABS <0.1 <0.1 <0.1 <0.1
(ISO 5 or better)
ISO 5 <1 <1 <1 <1
ISO 6 <3 <3 <3 <3
ISO 7 <5 <5 <5 <5
ISO 8 <10 <10 <10 <10
a
All operators are aseptically gowned in these environments (with the exception of
background environments for isolators). These recommendations do not apply to production
areas for non-sterile products or other classified environments in which fully aseptic gowns
are donned.
3
Alert and Action Levels
Table 4.4 Minimum standards in number of CFU for monitoring levels
Settle
Equipment
Plate 4 Operato
Air and Area Glove
EU Area Hour Gown
Levels Sample Surface Print
Grade Exposure Surface
(M3) Samples (5 Digits)
(diam. Samples
(24cm2)
90mm)
A Alert N/A N/A N/A N/A Not

Action >0 >0 >0 >0 applicabl
B Alert ** ** ** ** **
Action 5 10 5 5 5
C Alert ** ** ** Not Not

Action 50 100 25 applicable applicabl
D Alert ** ** ** Not Not

Action 100 200 50 applicable applicabl
Incidence rates are used to monitor overall performance and not part of release
criteria – Alert and Action levels are used for monitoring control.
3
Holistic monitoring of the microbiological profile to detect and respond to
escalation in bio-contamination transfer risk to Grade A.
Change emphasis from Surface Settle Plate Active Air
Reactive.
Grade A
Bio-contamination risk management
Contamination
event:
Move from reactive to proactive
RCA.
CAPA.
Batch loss?
Current Microbial Standards
Grade B
Holistic monitoring of profile recognise the relationship between zones
Grade C
Proactive
Risk Profiling and Proactive Response - RPPR
Increased risk to Grade A by Bio-contamination transmission through D>C>B to A
Risk profiling Holistic Proactive response

• cfu levels - holistic Monitoring to profile change &
• Microbiological flora
D>C>B>A D > C* > B > A increased risk to A
C* = Increase
bio-contamination CAPA – Investigate root cause
control and monitoring Corrective & to change in
in Grade C. Preventative microbiological profile
Action
Profile the measurable
cfu’s in Grade C to
Less emphasis on Grade A where zero cfu is expected
detect increased risk
and deviations are reactive – possibly with loss of batch
to Grade A.
3
RABS and Zonation
Unclassif ied Areas / z ones / PCCA
EU Grade C
ISO8 in operation
in operation
EU Grade B ISO7
RABS
EU Grade A
ISO 5
in operat ion

at Rest
Cleanrooms with RABS Separation Barrier Systems operated at positive

pressure to minimum EU Grade B / ISO7 background (in operation).
30
Isolators +Ve Zonation
Unclassif ied Areas / z ones / PCCA
EU Grade C
ISO8 in operation
in operation
Isolator +ve
EU Grade A
ISO 5
in operat ion

at Rest
Cleanrooms with Isolator separation barriers operated at a positive

pressure differential to minimum background EU Grade D / ISO 8 31
Hierarchy of Biological Reduction
Biological Reduction Hierarchy
• Sterilisation: Moist Heat, Dry Heat Gamma irradiation, ETO

• Penetrative processes fully referenced in pharmacopeia's delivering a defined sterility assurance
1 level (SAL)
• Automated Surface Sterilisation

• Non-chemical based automated surface sterilisation
2 • Chemical based automated Gaseous Surface Sterilisation in combination with residue free
cleaning to prevent chemical contamination transfer to products
• Automated Gaseous Disinfection (airborne and surfaces)
3
• examples include Hydrogen peroxide vapour –vH2O2/ VHP
• Semi-automated aerosol/ fogger disinfection (airborne and surfaces)
4
• examples include Dry fog, nebulisers
• Surface Manual Disinfection Processes; In-process efficacy qualification

• Surface Manual Disinfection Procedures: Laboratory qualified efficacy. in-process qualification
5 of agent application via procedures (SOPs). EM used to monitor impact on microbial control
3
Biological reduction metrics
Biological reduction is expressed as ‘Log10 reduction where (one) 1 log10

reduction is a 90% reduction in biological challenge population, or a division of
the population by ten. 6 log10 reduction is six steps with 90% reduction at each
step;
An example of 6log10 reduction would be starting from a spore population of
one million then following 6 x 90% population reduction steps this would be:
1,000000 spore population > (1 log10) 100000 > (2 log10) 10000 > (3 log10)1000
> (4 log10) 100 >(5 log10) 10 > (6 log10) 1 > additional process lethality /overkill
achieves > surface sterilization > then Sterilization at a Sterility Assurance level
(SAL) if the process is penetrative.
Typically such high biological/ spore populations would be considered for

biological indicators used to challenge the efficacy of a disinfection/
decontamination system/ process that has the ability to achieve 6log10 sporicidal
efficacy. Where pre-disinfection bio-burden is lower and there is no direct risk to
contaminate critical areas, surfaces or products lower levels of log reduction are
applied to qualify the efficacy of a disinfection process/ procedure. 3
Manual Cleaning & Disinfection
Manual Disinfection of classified and controlled areas
• Sourcing new disinfectants or sanitising agents

• Use of disinfectants in controlled areas and transfer of
pre-sterilised items
• Qualification of manual disinfection processes/ procedures
• Qualification of manual disinfection processes/ procedures
• Standard European approach
• Standard U.S. approach
• Recommended practice for laboratory testing of a disinfectant
for use in manual disinfection
Recommended practice for completion of laboratory testing by a site to support
introduction of a new disinfectant for use in classified and controlled areas. The
approach is based on an adaption of standard (generic) approaches for specific
use in pharmaceutical and hospital GMP/ cGMP Classified and controlled areas.
3
Semi automated aerosol (fogger) disinfection technology
Semi-automated disinfectant aerosol systems termed as Foggers,

Dry foggers, atomisers, have a role in cleanroom and controlled
area disinfection to improve the distribution, uniformity in
application of disinfection agents for large volumes / surfaces over
that of the manual application of agents.
3
Automated Gaseous Disinfection
• Automated Gaseous Disinfection, under validated conditions, provides

repeatable and robust biological decontamination of controlled areas/
zones; airborne and surfaces at relatively low temperature conditions,
typically below 30 degrees Celsius.
• It should be noted that Gaseous disinfection is a finishing step and

areas also require pre-cleaning to remove soiling layers that would
protect microorganisms from the surface disinfection process. Also
only surfaces that are exposed to the gaseous disinfection agent will
be disinfected.
• The Gaseous disinfection agents may vary but there is more limited in
choice when considering issues of material compatibility,
requirements for a residue free process together with operator/
personnel and environmental safety. 3
Hydrogen Peroxide Vapour (VHP) Gaseous H202 delivered hot at high
concentrations It For
Disinfection – Bench mark process optimisation of cycle time
it is key to prevent delivery
losses
Residue free process:
Aerate – re-evaporate molecules, Vaporise hydrogen peroxide at 1250C into
<500c
break hydrogen bonds, out gas small molecules (pico range - 10-12).
and break down to water and Mobile or integrated
oxygen H2O2 Generators
Optimum direct
injection for
Barrier systems
with Jet expansion
reducing
decontamination Different Vapour Delivery
temperature> 250C
Optimum Saturated Vapour
i
l
l
i
P
d
i
m
s
a
l
P
s
e
m
o
s
o
b
i
R
Inactivate virus, spores, bacteria, fungi, moulds.. Contact of H2O2 molecules on target surfaces . H202
Validate with BIs - 6log reduction. (2-6) invisible micron-layer using physical chemistry
(past dew point) as a delivery mechanism to target
contamination with nuclei formation of agent for
rapid kill - decontamination.
Kill Process
Manual Disinfection Transfer Hatches
& VHP Material Rapid Decon chambers
1. Load transfer cycle times 25 to 45 minutes (depending on Load).
2. Temperature protection, limits above 30 degrees C exposure. •Load and Clean
Carts included in
3. Interlock priorities selectable for GMP and Containment.
transfer solution.
100mm Vent
•Point contact
Load side Clean side
support cart-rack
designed to suit
process load.
•Uses one worst
case cycle for
Max-Min |&
Load Cart Cat Clean Cart
variable loads.
•H2O2 Generator
can be installed in
<<<< Reversible Interlock Priority >>>> remote location or
integrated.
Rules for Load Presentation In
Gaseous Disinfection with VHP
vapour conditions (past dew point).
Turbulent
Saturated
Vapour
Process requirements
• Point contact support
• No dead legs between items
• Surface area of load items characterised
• % of packaging material characterised
To provide the necessary load presentation suitable (by design) racking and
hangers are required that have point contact support and present loads with clear
paths for gas/ vapour movement between and around load items. Note: wire racking
or wire hangers provide point contact support, perforated sheet or strap hangers
occlude load surfaces from full exposure and gaseous disinfection.
3
Single Use Systems
Photograph courtesy of
Millipore Bioprocess division
Barrier Separation technology for
Aseptic Filling & Sterility Test
RABS OR Isolators
Open RABS Separate the most contaminating

source, people,
from
Sterile products,
critical
environments &
Closed RABS Isolators
surfaces
Isolated
Filling Filling Linessystems
Isolator Barrier and Sterility
and SterilityTest Isolators
Testing
Standard and modular systems are in development
+
Sterility testing Regulations;
‘No repeat testing’ unless False positive is proven.
Hardware
Equinox Isofit pump
for isolator
A Complete
solution for Steritest EZ filtration units
élimination of
False positives
and Mitigation
of business
Risk
High level of Gaseous

Culture media & Fluids
Disinfection Bis, Cis & H2O2
Containment & Cross Contamination control
Pharmaceutical Containment Hierarchy
• Biological safety rooms and cabinets: Biological safety Levels Rooms BL1,2,3,4 & Class
1,2,3 cabinets
1
• Containment of Biologically hazardous, toxic, pathogenic organisms, products/substances for
operator protection. Requirements detailed in Biosafety standards.
• AP1 – Active Pharmaceutical Ingredient containment: API Powder containment including

non sterile products
2
• Containment levels referenced in API micro-grams by cubic metre for operator protection.
Powder containment in Isolators (turbulent flow) and closed systems.
• Aseptic and Toxic containment in Aseptic processing of sterile medicines, drugs and drug
substances. Using Isolator technology with Safe Change Filter barrier containment and CIP /
decontamination features
3 • Product and operator protection to O.E.L. including containment for cross contamination control
• Aseptic and non pathogenic biological product containment in Aseptic processing of

sterile medicines, drugs and drug substances.
4 • Product protection and containment for cross contamination control using Isolator barriers.
• Aseptic processing with product protection
5
• Product protection using Barrier Separation Technology (Isolators and RABS).
3
Sterilising Containment by Zone segregation
Tunnel & pressure control with
dedicated Filtration.
Accum
Containment Hierarchy
1. API / AS – toxic powder containment.

Typically Negative pressure Isolation.
Filling
2. Aseptic – Toxic processing. Typically Low
positive pressure Isolation with toxic
Ref: ISPE containment design features.
3. Aseptic – Biological processing. Typically

low positive pressure Isolation with
Liquid fill molecular and particulate containment.
LYO fill
Capper
&
Decon ALUS ALUS
Buffer
Active
‘Mouse hole’ Lyo 1 Lyo 2
& Decon
Bio Hazard Aseptic – Containment Bio Hazard
Filling
Molecular Particulate
Personnel Gowning Concept courtesy of F Ziel

monitoring
Sterile Vial Rapid
Clean In feed Decon
Vials
EM plates & parts
Track & Trace
Track & Trace
Biological Barcoded Plates
Barcoded Plates Product
Photo: Courtesy of Pharmagraph
Filling Finished Product
Sterile Caps &

Stoppers Active
mouse
hole with
Filter
barrier
Buffer
Cap Cap
1. 2.
Lyo Interface 1. Lyo Interface 2.
Lyo 1 Lyo 2
Multiple Biological Product Contamination Risk Management
Principle; Separate risks of Filling-aerosols from Powder form (after Freeze drying)
(1) Risk mitigation steps for (3) Gaseous vH2O2
biological’s at molecular Bio-decontamination for
scale (can pass through HEPA Bio-Contamination control and
filters) using air dilution with denaturing biological’s for cross
validated clearance time . contamination control.
(4) Risk mitigation step for

biological’s in spill –
Contained clean up via wipes
and contained waste
handling.
Ulpa Filter Containment

Waste
Barrier>
CIP Fill
(2) Risk mitigation steps for RTP Alpha-Beta
Spill
biological’s In powder form: canister / bag.
Post Freeze drying / particulate
hazard control.
Aseptic – Biological Containment

Bio-contamination and Cross contamination principles
Aseptic manufacturing Zonation
Pressure differentials
Example (1): Aseptic processing pressure differential cascade
Barrier Filling line operated at positive pressure differentials
35pa +ve 50pa +ve 35pa +ve 25pa +ve 15pa +ve
EU Grade A EU Grade A EU Grade A EU Grade A EU Grade A
ISO ISO ISO ISO ISO
Crit ical Zone
Background: Isolator Line; Best practice Grade C / ISO 8 & RABS Line Grade B / ISO 7
Large Scale Filling
49
Aseptic – Containment manufacturing pressure
differentials e.g. processing biological products
Example (2): Aseptic – Containment processing pressure differential cascade
Barrier Filling line operated at positive pressure differentials
35pa +ve 25pa +ve 35pa +ve 25pa +ve 15pa +ve
EU Grade A EU Grade A EU Grade A EU Grade A EU Grade A
ISO ISO ISO ISO ISO
Crit ical Zone
Background: Isolator Line; Best practice Grade C / ISO 8 & RABS Line Grade B / ISO 7
Large Scale Filling
50
Open & Closed Design RABS
Open & Closed Operation RABS
RABS: Combination or Physical Open & Closed Operation
and Aerodynamic barrier. Using Open or Closed Design RABS.
Passive or Active Air management
Open Operation RABS
Open barrier door
operator interventions
Open A-ISO5 are risk assessed, A-ISO5
Design B –ISO7 justified, controlled
and monitored. Airflow
RABS protection at open
door.
Active Air management +ve Best practice: Closed Operation RABS

After set up and last
Bio-decontamination step
Transfer port SIP- AIP
Closed SIP-GIP closed after
barrier doors remain
closed for complete or GIP
Design use
aseptic processing
RABS Air over spill operation. Interventions
limited to only by barrier gloves /
transfer ports controlled access ports for
materials. SIP=Sterilise in place. GIP=Gassing in Place.
H2O2 Gaseous Disinfection (VHP) + GIP.
AIP= Aseptic/assembly in place.
Barrier Separation technology : RABS (Open & Closed)
Open Design RABS Down flow Closed Design RABS Down flow air
Air overspill to Room with circulates inside the closed Barrier
simple barrier typically with Air overspill at Transfer
manually decontaminated with connections – not a full physical
Autoclaved Out-Of-Place barrier around the Grade A ISO 5
Direct Product Contact Parts & Process Zone hence different to an
Feeder Bowls Isolator
Passive Open Design RABS with air Active Closed Design RABS with integrated
over spill to the ISO7 surrounding Area. H2O2 gassing.
Photograph courtesy of Boehringer Ingelheim Germany. Photograph courtesy of Franz Ziel, Germany for a Pharma project in Ireland.
Filling of Clinical trial batches of virus based product in Vials
A RABS Process solution for GMP compliance
Change rooms Grade B – ISO 7 Cleanroom + vH2O2 decontamination

Product
Pressure ‘Sink’ from
formulation
+ pa +++ Pa: Pressure regime
UDF airflow protection at
Open Design RABS Air-overspill access interfaces
Closed Operation RABS Sterilised

+++ inherent & corrective parts:
interventions.
Stopper bowl
+++ pa
+++ pa ++++ pa Caps bowl
++ pa Autoclave
+++ pa
Track-ways
Barrier Gloves
Pre-sterilised De-bag 2 > Filling & Capping Filled
Waste on exit
Stoppering product
Containers > Exit
Pre-packaged buffer
Sterile parts De-bag 1.
Pre-sterilised containers: Air-clean / alcohol disinfection transfer

vH2O2 + Single use systems (Product bag, lines) Air-clean / alcohol disinfection transfer
Airclean EM plates in VHP barrier packaging - vH2O2 decontamination transfer
Exit decontamination of outside of filled vials (virus clearance less than 30C)
Material VHP transfer chamber and Room VHP for

environmental viral clearance 53
Summary
1. Contamination control and Cross contamination control are
realised by combining contamination control attributes and good
practice. Control Strategies have increasing importance.
2. Zonation and Pressure control regimes will depend on Process

Barriers and Product types: Toxic, Aseptic, Biological
3. Biological reduction in disinfection programs, efficacy targets and

requirements in Contamination control are important to
characterise, risk assess and implement with EM monitoring to
verify target control conditions are achieved.
4. Intrusion into RABS Barrier systems is an important issue in Aseptic

processing, should be avoided in best practice but if justified needs
good design, good practice and full appreciation of risks. 54
Developments in Aseptic
Filling technologies
Wenzel Novak
Director pharmaceutical
research and development
groninger & co. gmbh
Overview
‒ Biosimilars
‒ Toxic & lyophilizated products
‒ Single-use
‒ Decontamination
‒ Nested objects
‒ Flexibility
• Small batches
• High-speed production
2
Biosimilars
Note:
2013 Worldwide pharma
840,000$mn => 1,200 ~ 0,15%
Source: Review on the Current and Future trends of Biosimilar Market in USA and India
Pankaj Goel1
1Business Development Department, Stellarix Consultancy Services Pvt. Ltd., India, 2012
3
Biosimilars
What’s that?
≈ follow-on biologics
≈ „generica“ of biopharmaceuticals
BUT:
Not exactly identical to originating biopharmaceutical
Synthesized by micro-organisms – different cell banks
and molecular clones
High molecular complexity
Sensitive to changes in manufacturing process
Impurities and by-products potentially have serious health
implications
Note: due to impurity nearly 150 death by a Biosimilar (heparin) in 2008
http://www.abda.de/fileadmin/assets/Arzneimittelkommission/Publikationen/PZ%20Nr%2001_2010_Lehren%20a
us%20dem%20Heparin-Skandal_%20Prof%20Alban.pdf
4
Biosimilars
Consistent requirements for approval in EU & US:
Patent expiration originator

Significant lower price than originator
API: amino acid sequence must be identical to originator’s
Source: http://aci.anorg.chemie.tu-muenchen.de/infotag/pics/proteinbild1.jpg
5
Biosimilars
Different approval procedures in EU & US:
EU:
thorough demonstration of "comparability" of the Biosimilar to

existing approved product
19 products approved (10/2014, source: vfa.de)
US:
Approval according to Patient Protection and Affordable Care Act

None approved yet acc. to that
6
Biosimilars
Differences on approval conditions (EU)
Requirement Generica Biosimilars
Documentation of pharmaceutical quality X X
Very detailed information about manufacturing process - X
and equipment
Proof of quality standards according to originator X X
Obligatory centralized approval procedure (EMA) - X
Decentralized approval (EU member states’ authorities) X -
Preclinical trials (pharmacodynamics) - X
Phase 0 Preclinical trails toxicology - X
Phase I clinical trials X X
Phase III clinical trials Seldom X
Phase VI clinical trials _ X
7
Biosimilars
Period of market exclusivity of top ten
Source: Pharmaceuticals 2012, 5(12), 1393-1408; doi:10.3390/ph5121393

Biosimilars: Company Strategies to Capture Value from the Biologics Market
8
Biosimilars
Source: Review on the Current and Future trends of Biosimilar Market in USA and India
Pankaj Goel1
1Business Development Department, Stellarix Consultancy Services Pvt. Ltd., India
9
Biosimilars
Sensitive and sometimes wayward
Challenging filling properties (thixotropy, viscosity, sensitivity,…)
Proteins (= Biosimilars) are sensitive to:
• Temperature (e.g. high frictional heat during processing)
• Pressure
• Shear forces
Denaturation means loss of 2°, 3° and 4° structure and specific
characeristics such as:
• Solubility ( injectability?)
• Viscosity
• Pharmaceutical activity (?)
10
Biosimilars
Available filling systems - suitability for biosimilars
criteria Rotary piston Peristaltic Time-pressure Mass flow
High viscosity ++ - + -
Filling accuracy ++ + (+) +
Easy in production ++ + -- +
No system-IPC required ++ - -- ++
Product temperature ++ ++ - ++
CIP/SIP – compatible + ++ + (+) ++
Performance ++ + ++ -
Filling range + ++ ++ -
shear forces - + ++ ++
Disposable / single use ++ ++ - --
11
Toxic Products
CMR active products
• Zytostatic products
• Active vaccines
• Tetracyclines
• ACE-inhibitors
• Radioactive diagnosticals for e.g. tumor detection
• Glucocorticoids
• …
Products with high levels of volatile solvents also need special
precautions in manufacturing (e.g. danger of explosion)
12
Toxic Products
Challenges in production
- Protection of the product & equiment
- Protection of the employees (crosscontamination)
- Protection of the users & patients (residuals)
Source: www.cleanroom-service.com/html/angebot.html
 At least shielding of the filling &closing unit of the production

line
suitable systems:
− Restricted access barrier systems (RABS)
• Open RABS
• Closed RABS
− Isolators technology
13
Toxic Products
Open RABS Closed RABS
Integrated sterile air handling unit Integrated sterile air handling unit
pressure controled pressure controled
Additional HEPA filter system LF air circulation (HEPA included)
Cooling system integrable Integrated air condition systems
Restricted Access: doors locked Restricted Access: doors locked
Air supply via cleanroom ( open) Separated air supply ( closed)
No separated H2O2 deco possible Separate disinfection possible
- Contamination-free filter change
(e.g. bag in – bag out)
- WIP
- For toxic and dusty products
- Real alternative to an isolator
14
Toxic Products
Isolators
Completely enclosed aseptic working area
− Automated WIP system
(spray cleaning heads and spray lances inside)
− Separate air return ducts with
integrated spray nozzles
− Double HEPA filter stage in air return
ducts with safe change filter system
(bag in – bag out)
− CAVE: loss of isolating properties when
opened  Decontamination obligatory
15
Toxic Products
Fill-Finish line
- No vacuum
- Positive pressure gradient from cleanroom to isolator & safety
precautions for malfunction (reference pressure for all systems: 0Pa)
- Additional post-closing outside-decontamination unit
Transfer Rotation
unit plate . Filling & closing Outside
Infeed & washing Sterilisation tunnel decontamination
Warming-up Heating unit Cooling unit
unit
Enviroment
PNP
p=0  p1=0Pa p=10Pa p=+2Pa p=+2Pa p=-15Pa p=+

p= p=
-14Pa +29Pa
16
Lyophilisated Products
Lyophilisation:
removal of water (even water of cristalization) through sublimation under
vacuum after very quick freezing of the product
Sublimation:
direct phase transition
from solid to gaseous state
Source: www.splung.com
17
• Quality of product remains unchanged

Source: www.primegene.com
• Drying products without changing the structure of molecules

• Even microorganisms can be „revitalized“
18
Process risks
Freezing process:
• Filling level of vials too high release of product during
expansion (freezing process)
Vacuum porcess:
• Unsuitable evacuation speed
• Explosion of unsuitably closed containers
• Breakage of damaged containers
…
→ Cross-contamination of other containers of the batch
19
Detoxication of containers
Removal and inactivation (chemically) of
contaminants without wetting the crimping cap
©© SGD
20
Single-use
Single-use-systems in (BioTech) - Manufacturing
• Media preparation
• Cell cultivation
• Bioreactors
• Purification
• Filtration
• Formulation
• Product storage
• Bulk filling
21
Single-use
solutions: complete disposable filling path
22
Single-use
Components for disposable systems
23
Single-use
Single-use not available yet
• Mass Flow
• Time Pressure
Single-use already standard
• Peristaltic Pump
• Diaphragm Pump
Single-use an option
• Rotary Piston Pump
• Filling Needle
By Ryan O'Connor (Ryan O'Connor) [CC-BY-SA-3.0
(http://creativecommons.org/licenses/by-sa/3.0) or GFDL
(http://www.gnu.org/copyleft/fdl.html)], via Wikimedia
Commons
24
Single-use
Benefits of single-use fill finish
• Reduce investment costs
• Reduce change over time
• Eliminate CIP / SIP
• Eliminate Cross-Contamination
• Reduce (re)-validation activities
• Reduce qualification activities
• Reduce time to market
25
Single-use
Which material will work best?
− Plastics?
− Stainless steel?
− Combination of different materials?
• Leacheables
• Extractables
• USP ClassVI - conformity
• Biocompatibility / cytotoxicity
• Particulates
• Steadyness
26
Single-use
Singel-use or traditional approach
CUSTOMER DATA CIP/SIP Single Use System
Investment in $500,000 --
equipment (incl. $200,000 ancillary costs) (even less equipment costs)
Setup (incl. connections) 2 hours 45 minutes
CIP + SIP-cycle 40 + 75 minutes --

(arrives ready to use)
Cool down cycle 75 minutes --

(ready to go)
cleanup 1 hour 15 minutes
Post-Use CIP 40 minutes --

(dispose it)
~ 7 hours & $500k 1 hour & cost of assembly

Summary (qualification & re-validation efforts
(easy storage)
are not included)
27
Single-use
Complete single-use product path
28
Single-use
Disposable filling system = installation on filling line
29
Decontamination
Transfer of cfu into sterile container
Inside contaminated due to transport damage (e.g. pinholes)
Typical material: Tyvek™, HDPE, LDPE
(assuming a proper sterilization and packaging closure)
30
Decontamination
Transfer of cfu into sterile container
Contaminant is carried over from the outside into a primary
container during opening process
A spore made it into a syringe

31
Decontamination
from a very black area (truck)
to unwrapping in class C till filling in class A
32
Decontamination
Regulatory requests by Authorities
APPENDIX 1: ASEPTIC PROCESSING ISOLATORS
(“Contains Nonbinding Recommendations”)
…
D. Decontamination
…
2. Efficacy
… Process development and validation

studies should include a thorough determination of cycle capability. The characteristics of these agents generally preclude the
reliable use of statistical methods (e.g., fraction negative) to determine process lethality (Ref. 13). An appropriate, quantified
Biological Indicator (BI) challenge should be placed on various materials23 and in many locations throughout the isolator,
including difficult to reach areas. … Normally, a four- to six-log reduction can be justified depending on the application. … For
example, demonstration of should be sufficient for controlled, very low bioburden

materials introduced into a transfer isolator, including wrapped sterile supplies that are briefly exposed to the surrounding
cleanroom environment.
…
33
Decontamination
procedure note
zone concept no disinfection
not sporicidal; difficult
spraying alcohol
validation; 102 kill
15min - 6h
Aerosol (VHP) /
erosion of material
wetting by H2O2
Residuals (Tyvek)
E-beam Radicals; oxidation; radiation
max. killing rate 10³
UV-light
shadowing effects
Plasma Qualification by Biostripes
Noxilicer New technology
34
Plasma Decontamination
Decontamination mechanism
• UV-light DNA damage
• etching cracking of molecules

• Ions & radicals erode spores
• Takes a few seconds to fully
erode a spore membrane
• Chamber-self-deco.
35
Plasma Decontamination
Installation
36
Nested objects – classical
37
Nested objects
38
Nested objects
39
Nested objects
40
Nested objects
41
Small batch: Benefits
Flexibility
Easy adaption to changes of:
Containers, Processes, Performance, Layout, Location, …
http://thumbs.dreamstime.com/x/buntes-
Regulatory requirements
cham%25C3%25A4leon-%25C3%25BCber-wei%25C3%259F-
11662189.jpg
Small batch to midsize production

Short market introduction
Repeatability (IQ, OQ, PQ)
Integrated automation + docu
(Standarddocumentation „ready to use“)
short delivery time & start-up phase http://mmrstrategy.com/wp-content/
uploads/2013/03/market-new-product.png
43
Small batch: modular concept
• 3 standardized isolators
• Modular filling equipment designed for isolator
Isolator
Production isolator Lyo isolator oRABS
add-on
manual vial 1% capping Freeze dryer capping
auto. syringe 100% Additional adaption by format parts:

• Peristaltic and/or rotary piston pump
cartridge • Single-use system • Filling volume
• Vacuum filling and stoppering
• Container dimensions made of polymer
Sketch not to scale! or glass by several suppliers
44
Capping inside or outside line?
45
Particulates
Amount of particles on:

Vial opening level Vial bottom level
Mp1 particles amount Mp1 particles amount
≥ 0,5 µm 24 ≥ 0,5 µm 2328
≥ 5,0 µm 0 ≥ 5,0 µm 12

≥ 0,5 µm 312 ≥ 0,5 µm 5268*
≥ 5,0 µm 0 ≥ 5,0 µm 84*

≥ 0,5 µm 0 ≥ 0,5 µm 0
≥ 5,0 µm 0 ≥ 5,0 µm 0

≥ 0,5 µm 12 ≥ 0,5 µm 10
≥ 5,0 µm 0 ≥ 5,0 µm 0
46
Keep: Reduce: Gain:
• Footprint • Flexibility
Known processes
Approved solutions • Training - on container
Product quality • Quali. / Vali. - on location
Product safety • Investment • Reproducibility
- on equipment
- on processes
• Investment safety
47
Small batch: Nested objects
Nested Vials, Cartridges and Syringes
48
Small batch: IPC
Optional 100% IPC possible
49
Small batch: Toxic products
You can anytime later modify
the existing Isolator to run
toxic products
(with catalytic converters)
50
Small batch: Isolator variation
Standard module 2,35m / 90in
Adding module 1,20m / 50in (no individual VHP source)
Freeze-dryer module 2,35m / 90in
Capping module 1,04m / 40in (oRABS)
51
Processing: bulk material
52
Processing: nested objects
Each weight object has to be

removed from nest
53
Production: nested objects
• High & medium speed versions available

• All nested objects (syringes, vials, cartridges)
• Flexible modular concept
• 100% IPC up to 400/min; with single-object rejection
• For all available barrier concepts
(o-RABS, c-RABS [active, passive] Isolator, Zone concepts, …)
54
Thank you very much for your attention!
Wenzel Novak
Director pharmaceutical
research and development
groninger & co.gmbh
Death Kinetics – survivor curves
Typical DK profile from Moist Heat Typical DK profile from Chemical based
Sterilization - Autoclaving Gaseous Disinfection/ Surface Sterilization
– GD/GS; VHP
Reference taken from PDA TR 51

BIs for Gaseous decontamination
47
FRANZ ZIEL GmbH
Fully Integrated Gaseous Disinfection GD-VHP Systems
Short VHP cycle times = Less production downtime

Stage 1 Kill Direct injection, no recir & Stage 2 Kill, full recir.
Heat traced pipe
VHP (controlled and monitored)
Generator
Recirc fan
VHP conc. (HC)
Diff. Press.
CG screen
HEPA Filter PTFE HEPA Filter PTFE
Rotating nozzle
T(VHP) underneath the
=50°C
CG screen
HMI
T(VHP)
=25°C
HMI Isolator Process machine

Process area
(grade A)
H2O2 bottle
with RFID
48
There are different Cleaning qualifications between Gaseous Disinfection GD-VHP of
the Barrier (non product contact parts) and Gaseous Surface Sterilisation GS-VHP of
Feeder Bowl surfaces. Pre-surface sterilisation cleaning residues must be verified as
removed or trace elements that will not past to products as a chemical contamination,
possibly in compound with hydrogen peroxide.
Filling Lines: Gaseous Sterilization GS-VHP for surface sterilization by Gassing–in-

place (GIP) of surfaces that contact direct product contact parts e.g. Stopper bowls;
Reducing pre-production aseptic procedures.
No operator intervention after last Bio-decontamination (GIP) step.
Gassing-in-place of: Hoppers – feeder bowls

Track ways for containers, cap closures.
Barrier gloves. feeder transfer chutes.
FRANZ ZIEL GmbH
Gassing cycle Development ( GCD): Gaseous Disinfection (GD-VHP) of Barrier and

Equipment surfaces & Surface Sterilization (GS-VHP) of Stopper bowls/contact parts
Gassing Cycle development BI Pre-use Qualification Studies live
Key:
Protocol/ scientific rationale Enumeration + System D values with vaporised
hydrogen
Pre-study: Set Start GCD-2 parameters peroxide (VHP)
Cleaning validation From Factory GCD stage 1
before Gaseous Sterilization GS-VHP
(surface sterilization) studies
Set/ Map BI Challenge locations Pre-VHP studies
of Stopper contact parts/ surfaces Safety review/ briefing
Risk based, Temps (Hot/Cold spots)
1. Conditioning time study 2. Gas Distribution (CIs + BIs) 3. System resistance (A): BIs
Temperatures and starting %rh + Gassing profile study (ppm) Kill time (KT) + Death Kinetics (DK)
4. Optimize System resistance (B) 5. Full BI challenge study: 6. Overkill determination

BIs: Kill time (KT) + Death Kinetics (DK) all locations: minimum overkill Based on iterative results/ science
Possible Rogue 7. Full BI challenge study 8. Sub lethal study: Full BIs
BI investigations Overkill parameters Performance Characterization study
9. Aeration and cycle end point studies: 10. Results analysis of VHP cycle GCD
Verification ppm target (GD-VHP) + Surface Sterility (GS-VHP) parameters to set PQ cycle Final report
James Drinkwater VHP GDCD – CYCLE DEVELOPMENT MATRIX OF STUDIES 50

VHP Residuals and Product impact testing
Study plan
Expose empty product vial to VHP Gaseous residuals at VHP

Exposed cycle end points of 0.3ppm and 0.1ppm add un-exposed test
empty Vial water, rinse (shake) & complete Amplex Red (HRP) analysis.
Product Surrogate Expose filled vial (with product surrogate), sample and
‘S-product’ in Vial analyse for presence of H2O2 (limit of detection 15 ppb)
Expose stopper to VHP Gaseous

Stopper Exposure
residuals, insert into un-exposed water
addition to control vial
filled/ vial, sample and analyse.
Stopper exposure Expose stopper and Filled Vial.

addition to exposed Insert stopper, contact fill with
‘S-product’ in vial stopper, sample and analyse.
Biological Product ‘Spiking’ Spike biological product with ‘Worst case’ H2O2
study and VHP residual residual found over study series. Analyse
impact assessment product impact: efficacy, quality/ stability, safety.
James Drinkwater VHP Residuals Study Plan 51

FRANZ ZIEL GmbH
Isolator & Material load
Gaseous Disinfection
Sterility Test and Small Batch Aseptic There are two types of VHP Gaseous
processing Isolators Disinfection Cycles:
1. Gaseous disinfection of the

complete Barrier: Decon Hatch
(inner door open to expose seal
surfaces) and Process Zone
together – includes any installed
equipment e.g. Sterility test pump.
2. Gaseous Disinfection of the Loads

(outer packaging surfaces of sterile
components) in the Rapid Decon
Hatch.
The Full module is qualified with an

Aseptic hold: time between Full Barrier
+ Rapid Decon Hatch VHP cycles.
In routine operation Load transfer
cycles are used without compromising
Sterility Test Isolator the Grade A aseptic conditions.
James Drinkwater FZ In-House VHP Training 52

Manual Disinfection Transfer Hatches
& VHP Material Rapid Decon chambers
1. Load transfer cycle times 25 to 45 minutes (depending on Load).
2. Temperature protection, limits above 30 degrees C exposure. •Load and Clean
Carts included in
3. Interlock priorities selectable for GMP and Containment.
transfer solution.
100mm Vent
•Point contact
Load side Clean side
support cart-rack
designed to suit
process load.
•Uses one worst
case cycle for
Max-Min |&
Load Cart Cat Clean Cart
variable loads.
•H2O2 Generator
can be installed in
<<<< Reversible Interlock Priority >>>> remote location or
integrated.
Rules for Load Presentation In
Gaseous Disinfection with VHP
vapour conditions (past dew point).
Turbulent
Saturated
Vapour
Process requirements
• Point contact support
• No dead legs between items
• Surface area of load items characterised
• % of packaging material characterised
To provide the necessary load presentation suitable (by design) racking and hangers
are required that have point contact support and present loads with clear paths for gas/
vapour movement between and around load items. Note: wire racking or wire hangers
provide point contact support, perforated sheet or strap hangers occlude load surfaces
from full exposure and gaseous disinfection.
54
Summary
Options Fully Integrated

of Environmental
monitoring systems.
Single Wall and
Double Wall Barrier Classification &
designs Monitoring
Design features and Isolators have

Contamination become best
control attributes Aseptic practice for Sterility
are in different Processing Testing to manage
combinations for risks of false
process types applications positives
with Barrier
Technology
Real-Time Microbial
Detection RMM
How a Real-Time Viable Particle

detector provides benefit today
Stanley Thomas
PHSS,Mumbai
Understand the Measurement
Active Air Sampling
Few clauses on
Environmental
Monitoring Frequent in Operation?
ISO 14698-1
TSA Media
Efficiency 20%?
Sampler Aerosol Collection Efficiency
Vendor A Vendor B Vendor C
4-5 Days to a result…
PERFECT
© TSI Incorporated 11/20/2014
2
Innovation!
Real-Time Airborne Viable Particle Monitoring
New family of RMM: Optical Spectroscopy

Laser Induced Fluorescence (LIF)
Primary benefit: Real-time, high time resolution results
Seconds

3
BioTrak: Three portable instruments in one
Inlet Current Technology-
Particle ISO 21501-4 compliant particle counter 28.3

Counter
lpm
Particle NEW!
Concen-
trator
Viability detector- Laser Induced
Fluorescence
HEPA filter
Viability
Detector Current Technology-
Collection
filter 37mm Collection filter for speciation of
optically analysed particles

4
BioTrak: Real-Time Aerosol Optical Spectroscopy
Determine viability using 3 parameters
Scattered Light
Viable cell metabolites

tryptophan, NADH, and
flavin’s (riboflavin)
Particle
Counter fluoresce when excited by
ultra-violet light
Particle
Concen-
trator
HEPA filter
Viability
Collection
Detector
Fluorescence B
filter
Fluorescence A

5
BioTrak: Discrimination
2 Parameters 3 Parameters
Discrimination is much better when utilizing 3 analysis parameters

Tradeoff between sensitivity (low number of false negatives) and specificity (low
number of false positives)
Data illustrated was obtained from pure lab samples, environmentally obtained data exhibit less clear
differentiation.

6
Particle
BioTrak: Particle Analysis and Speciation

Counter
Particle
Concen-
trator
HEPA filter
BioTrak Integrated Collection Filter Viability

Detector
Collection
filter
Load Collection Filter Insert Filter Holder Lock Filter Holder
Up to 9 Hrs continuous air flow

Load Agar Plate Incubate and identify

7
Vendor Validation-The Challenges
Rapid Method
Compendial Method
Active Air Sampling Comparison: Equivalent or Better
ISO 14698-1 USP 1223, EP 5.1.6, PDA TR33 : 2013
DMF
Submittal to
Real Time Aerosol Viable US FDA
Detection
8
Application Road Map
“The Innovation Highway”
Real-
time
Monitoring
release
Locations
Confidence in the measurement
Air Exchange
Optimization Risk Analysis
Comparability
Vendor Studies
Validation
Validated
Intervention
Operator Free In-
Risk Based Process
Root cause Room Training
Measurement
Investigations Release
Immediate benefit Long term goal/benefit

9
Real World Example

10
Targeted Monitoring
US FDA ISO 7 Area
US FDA ISO 7 Cleanroom
Single mold spores seen infrequently using

active air samplers, mostly zeros, zone is
within US FDA ISO 7 limit of 10 CFU/m³
Difficult to get to the root cause of the mold

spores
Plan: Targeted Monitoring
Run BioTrak detector continuously (1 minute

samples) for ~2Hrs at a single location
Run active air sampler at the same time, taking

samples more frequently than normal
Run site optical particle counter at the same

time

11
Particle
Counter
Particle
Concen-
trator
HEPA filter
Viability
Detector
Collection
filter
111 minutes or 3.14m³ of

air sampled onto the
BioTrak collection filter:
following incubation 8 mold
colonies were grown
5 x 0.16m³ or (total 0.8 m³) Active Air Samples

- 2 x Single mold colonies THE SAME MOLD AS
GROWN ON THE BIOTRAK COLLECTION
FILTER
12
Interpreting the data…

13
Current measurement technology
Particle
Counter
Particle
Concen-
trator
HEPA filter
Viability
Detector
Collection
filter
US FDA ISO 7 0.5 µm Limit: 10,000/ft³
US FDA ISO 7 Micro Limit: 10 CFU/m³

14
Possible conclusions from traditional
data US FDA ISO 7 0.5 µm Limit: 10,000/ft³
Total particulate counts are
US FDA ISO 7 Micro Limit: 10 CFU/m³
in control @ 0.5 µm, no
noticeable adverse trends
Increased frequency of
Active Air Sampling is
detecting mold more often…
Mold recovery at the

beginning of testing
Active Air Sample individual

results and average values
are within action limits
Is there even a problem?

If so, is there enough information to help look in the right place?

15
New and traditional data- Real-Time
Viable Counts and Plate Counts
A B
C
D E

16
Possible conclusions from new data
Active Air Sampling is
missing events
Real-time Airborne Viable A B

Counter is detecting more
events
Possible significant event at

the END of testing??
C
Active Air Sample individual
D E
results and average values
are within ISO 7 action limits
Is there even a problem?

If so, is there enough information to help look in the right place?

17
4 consecutive BioTrak
detector samples
showing viable
particle recovery
18
Root Cause Investigations
Same BioTrak detector was then configured to:

Sniff out the microbiological contamination source
Investigation Tool - “Geiger Counter “ mode
1 Beep = 1 Airborne Viable Particle

19
Targeted Environmental Monitoring
• ISO 7 targeted monitoring with the BioTrak detector
identified activities that generated microbiological airborne
1 contamination
•BioTrak detector collection filter and Active Air Sampler
2
recovered the same mold spores
•BioTrak detector then used as a sniffer to find precise location

of contamination source
3

20
Application Road Map
“The Innovation Highway”
Real-
time
Monitoring
release
Locations
Confidence in the measurement
Air Exchange
Optimization Risk Analysis
Comparability
Vendor Studies
Validation
Validated
Intervention
Operator Free In-
Risk Based Process
Root cause Room Training
Measurement
Investigations Release
Immediate benefit Long term goal/benefit

21
Questions
stanley.thomas@tsi.com
© TSI Incorporated
22
GMP Compliance
Ganadhish Kamat
24/11/14
Current scenario
• Many companies going through regulatory actions
– Warning letters
– Import bans
• Major issues
– Data integrity
– Sterility assurance
– Inadequate investigations
• Inspections are not the same
– No advance intimation
– Focus on data integrity
– Air of suspicion
– Fear / stress
• Refusal to accept truth
– Conspiracy theories
What lead to the situation?
• Mindset of “Managing the audit”

• Complacency - “we have done it before”
• Lack of Management involvement in Quality review
• Unwillingness to accept bad news
• Cultural issue – might lead to unethical behaviour
• Lack of transparency
• Lack of process understanding
• Gap between Indian regulations and global requirements
What actions are required
• Identification of right quality metrics & review by top

management
• Moving from manual to electronic data acquisition
• Supporting investments for improving compliance
• Building right culture in the organization with Zero
tolerance for unethical behavior
• Getting to root cause rather than treating symptoms
• Transferring learnings from one site to other sites
• Aligning Indian drug regulations with global standards
Regulatory inspection summary
MHRA Top 10 Critical/Major observations
2008 – 2010
Investigation of anomalies 86
136
Quality Management 69
79
Investigations - CAPA 66
88
Change control 62
99
Documents - PSF/SOPs 55
79
2009-10
Complaint & recalls 44
82
2008-09
PQR 37
53
Batch release procedure 33
63
Self Inspection 17
23
Risk Management 10
17
0 50 100 150
Courtsey : Ms Di Morris
2013
Potential for contamination 16
Vendor Audits 16
Change control 16
Training 12
Design & Maintenance of equipment 11
Manufacturing documentation 11
0 5 10 15 20 25 30
Investigation tops the list since 2008

Top 10 deficiencies in FDA 483
Investigations
• Investigation is important part of Quality system
• Failures or non-conformities are common in

Pharmaceutical manufacturing
• Investigations are necessary to –

– To identify the cause and take corrective actions
– To identify other similar situations and take preventive actions
– Continuous improvement
– Regulatory requirement
All our equipment & processes are fully
validated
Why do we have
failures?
Current Approach to Validation
At best a snapshot!
Guidance driven
Lot of data generation

Process
Understanding
Validation
No Real Objective
Assessment of Outcomes!
What is its Real Value?
©Benson Associates
Current validated process
Lack of process understanding

All variabilities not identified and their impact on process and
product quality not evaluated.
All critical process parameters are not identified and adequately
controlled
Control strategies are not based on scientific risk assessment
Operating ranges given instead of set points
Various permutations of parameters can result in variable
output.
Process to handle exceptions not described
High operator dependence, hence prone to human
errors
Quality Control - How Relevant?
When there are manufacturing problems

• Questions Asked • Information Available
• Physical attributes • Moisture
• Blending performance • Colour
• Particle distribution • pH
• Segregation • Assay
• Flow • Related Impurities
• Homogeneity etc. • Hardness

• Dissolution etc..
Why do we have failures?
Variable Inputs
cGMP Fixed Fixed Fixed Univariate

Process Validated Product Testing
Specifications Process Specifications Methods
Produces Variable Product

Causes of failure or variation
• Assignable causes
– Causes can be identified and eliminated
• Human error
• Machine problem
• Material problem
• Deviation from process
• Environment
• Measurement error (Laboratory error)
• Common causes
– Random causes that we cannot identify
– Unavoidable
– Low process capability (Poor design or robustness issue)
15
Investigation
Six Sigma method of problem solving
Define Define the problem and customer

requirements.
Measure defect rates and document

the process in its current incarnation.
Control Measure
Analyze process data and determine
the capability of the process.
Improve the process and remove

defect causes.
Control process performance and

ensure that defects do not recur.
Improve Analyze
Key Investigation Skills
• Product & process understanding
• Thorough equipment understanding
• Risk assessment
– Identification of sources of variability and their impact on product
quality
– Data to be collection based on Risk assessment
• Statistical tools
• Analytical ability for data analysis & meaningful
conclusions
• Team approach
• Presentation of findings
How to improve process
understanding?
Validation - Lifecycle approach
– Stage 1 - Process design
• Defining commercial process based on the knowledge
gained through development & scale-up activities.
• Identifying the sources of variability and establishing
controls (DOE / Risk assessment)
– Stage 2- Process Qualification

• Confirmation of capability of process to result in
reproducible manufacturing (Performance
Qualification)
– Stage 3- Continued Process verification

• Ongoing assurance during routine production that the
process remains in a state of control (Statistical
trending)
20
Desired validated process
Thorough understanding of equipment & process
All variabilities identified and their impact on process and
product quality understood.
All critical process parameters are identified and adequately
controlled
Control strategies based on scientific risk assessment
Operating set points specified instead of ranges along with

process to handle exceptions
Low operator dependence.
Ease of finding the causes in case of failures
Statistical tools
SQC Tools for investigation
• Brain storming
• Five Whys?
• Process flow diagrams
• FMEA
• Cause and Effect Diagram
• Histogram
• Pareto Chart
• Scatter Diagram
• Regression analysis
• Fault tree analysis
• Design of Experiments
• Control Charts
23
Application of SQC tools
Yes DOE
Record Implement NO Test

changes needed More detail process
needed?
changes options
NO
Define Yes
Identify Analyze NO
data to Collect Analyze Need for Improved
probable current C/A? enough?
be data data
causes process
collected
BRAINSTORM PROCESS RECORDS PARETO Yes
CAUSE /
FLOW EFFECT HISTOGRAM SCATTER
5 WHYS?
DIAGRAM DIAGRAM REGRES’n
FTA Record
FMEA Establish regular
unusual
events process monitoring
CONTROL CHARTS
24
Brain storming
Generation of ideas
Involvement of people
Allow people to speak without interruption
Random / sequential
Note down all the ideas without elimination

Five Whys?
• The 5 Whys is a questions-asking method used to
explore the cause/effect relationships underlying a
particular problem.
• Ultimately, the goal of applying the 5 Whys method is to

determine a root cause of a defect or problem.
• Keep asking Why till you reach root cause

Five Why example
Problem : Dissolution failure in tablets
Why it has happened ?
High DT Why is that?
Over lubrication Why is that?
More mixing in Force feeder Why is that?
Slow M/c speed with high feeder RPM Why is that?
Parameters not defined in BMR

Process flow diagram
Helps in Process understanding
Identifies critical steps, critical parameters, control

measures
Helps in identifying the data to be collected
Helps in identifying probable causes

Fault Tree Analysis
FTA Template
• Graphical representation of the major
faults, the causes for the faults, and
potential counter measures.
• Helps identify areas of concern for

new product design or for
improvement of existing products.
• Helps identify root cause of failure
• Helps identify corrective actions.
• Can be useful both in designing or

investigation.
Cause & Effect Diagram
•Developed by Kaoru Ishikawa Ishikawa / Fishbone Template
•Used to explore potential causes

(6 M’s) that can result in single Measurement
Measurement Methods
Methods Machinery
Machinery
undesirable effect (UDE).
•Potential causes arranged

according to hierarchy UDE
Causes, inputs,
or sources
•Helps in identifying potential of variation
problem areas under each of 6

M’s Manpower Materials Milieu
Manpower Materials Environment
UDE is an Un-Desirable Effect

Failure mode effect analysis
Scientific Risk assessment of process steps
Analyzes each step with respect to its impact on the

quality, probability of occurrence & detectability
Helps in filtering of probable causes

Tools for data analysis
Histogram
Pareto analysis
Scatter plots
Regression analysis
Control charts
X-bar, R, Sigma, Run charts for variables
c, p, np charts for discrete data
Useful for
Process monitoring
Trend analysis of past data
Monitoring effectiveness of CAPA

Data evaluation
Critical information to be reviewed
• Process flow
• Development report
• Forced degradation study & degradation profile
• Past history
• Material usage / left over stock reconciliation
• Critical process parameters & controls
• Trends of process parameters, process timing, hold time
• Yields
• Machine logs
• Distribution records
• Quality trends, Process capability
• Stability data (exhibit & commercial batches)
• Method validation & transfer data
Assay failures
• Correctness of Formulation
– Label claim / Salt / Water molecule / Batch size
• Correctness of quantities
– Weights / reconciliation of left over / yields
• Working standard
– Response comparison / WS changes / Other batches
• Loss / gain of material
– Yield / water content / physical verification
• Segregation
• Sampling technique
• Sample solution preparation
Failure in RS
– Pathway of formation / Structure / Control measures
• Forced degradation study
• Manufacturing conditions
• Solution stability
– Testing conditions
• Past trend
• Stability data (exhibit / commercial)
• Possibility of contamination
– Testing / manufacturing
DR failures
• Verification of dissolution medium
– pH / Degassing
• Critical component quality
– Release polymers, binders, disintegrants
• Critical process parameters
– Granulation (Power / Current, PSD, BD / TD)
– Mixing (Over lubrication)
– Compression (Speed, force feeder, compaction force)
– Coating (Air flow, inlet temperature, bed temperature, exhaust
temperature, RPM, spray rate, distance of spray gun, left over
solution, weight gain)
– Capsule filling (machine setting, machine principle)
Corrective & Preventive
Actions
What is CAPA?
• CORRECTIVE ACTION
– Action to eliminate the cause of a detected non-conformity or
other undesirable situation
– Corrective action is taken to prevent recurrence of non-
conformity
• PREVENTIVE ACTION
– Action to eliminate the cause of a potential non-conformity or
other undesirable potential situation.
– Preventive action is taken to prevent occurrence of potential
non-conformity
(ISO 9000:2005, ICH Q-10)

Investigation report
What should be included?
• Problem definition
• Discussion on analytical results / observations
• Summary of data reviewed
• Conclusions based on data review
• Experimental plan
• Summary of results of experiments
• Discussion & Conclusion of experiment results
• Final conclusion about root cause
• Corrective & Preventive actions
• Batch disposition
Summary
• Transparency & all time compliance
• Validation as life cycle approach

– Knowledge gain about equipment & process
– Robust process design
• Key skills for investigation

– Domain knowledge
– Analytical ability
– Systematic approach (DMAIC)
– Statistical tools
– Report / Presentation
GMP Compliance
Ganadhish Kamat
24/11/14
Current scenario
• Many companies going through regulatory actions
– Warning letters
– Import bans
• Major issues
– Data integrity
– Sterility assurance
– Inadequate investigations
• Inspections are not the same
– No advance intimation
– Focus on data integrity
– Air of suspicion
– Fear / stress
• Refusal to accept truth
– Conspiracy theories
What lead to the situation?
• Mindset of “Managing the audit”

• Complacency - “we have done it before”
• Lack of Management involvement in Quality review
• Unwillingness to accept bad news
• Cultural issue – might lead to unethical behaviour
• Lack of transparency
• Lack of process understanding
• Gap between Indian regulations and global requirements
What actions are required
• Identification of right quality metrics & review by top

management
• Moving from manual to electronic data acquisition
• Supporting investments for improving compliance
• Building right culture in the organization with Zero
tolerance for unethical behavior
• Getting to root cause rather than treating symptoms
• Transferring learnings from one site to other sites
• Aligning Indian drug regulations with global standards
Regulatory inspection summary
2008 – 2010
136
79
88
Change control 62
99
79
2009-10
Complaint & recalls 44
82
2008-09
PQR 37
53
Batch release procedure 33
63
Self Inspection 17
23
Risk Management 10
17
0 50 100 150
Courtsey : Ms Di Morris
2013
Potential for contamination 16
Vendor Audits 16
Change control 16
Training 12
Design & Maintenance of equipment 11
Manufacturing documentation 11
0 5 10 15 20 25 30
Investigation tops the list since 2008

Top 10 deficiencies in FDA 483
Investigations
• Investigation is important part of Quality system
• Failures or non-conformities are common in

Pharmaceutical manufacturing
• Investigations are necessary to –

– To identify the cause and take corrective actions
– To identify other similar situations and take preventive actions
– Continuous improvement
– Regulatory requirement
All our equipment & processes are fully
validated
Why do we have
failures?
Current Approach to Validation
At best a snapshot!
Guidance driven
Lot of data generation

Process
Understanding
Validation
No Real Objective
Assessment of Outcomes!
What is its Real Value?
©Benson Associates
Current validated process
Lack of process understanding

All variabilities not identified and their impact on process and
product quality not evaluated.
All critical process parameters are not identified and adequately
controlled
Control strategies are not based on scientific risk assessment
Operating ranges given instead of set points
Various permutations of parameters can result in variable
output.
Process to handle exceptions not described
High operator dependence, hence prone to human
errors
Quality Control - How Relevant?
When there are manufacturing problems

• Questions Asked • Information Available
• Physical attributes • Moisture
• Blending performance • Colour
• Particle distribution • pH
• Segregation • Assay
• Flow • Related Impurities
• Homogeneity etc. • Hardness

• Dissolution etc..
Why do we have failures?
Variable Inputs
cGMP Fixed Fixed Fixed Univariate

Process Validated Product Testing
Specifications Process Specifications Methods
Produces Variable Product

Causes of failure or variation
• Assignable causes
– Causes can be identified and eliminated
• Human error
• Machine problem
• Material problem
• Deviation from process
• Environment
• Measurement error (Laboratory error)
• Common causes
– Random causes that we cannot identify
– Unavoidable
– Low process capability (Poor design or robustness issue)
15
Investigation
Six Sigma method of problem solving
Define Define the problem and customer

requirements.
Measure defect rates and document

the process in its current incarnation.
Control Measure
Analyze process data and determine
the capability of the process.
Improve the process and remove

defect causes.
Control process performance and

ensure that defects do not recur.
Improve Analyze
Key Investigation Skills
• Product & process understanding
• Thorough equipment understanding
• Risk assessment
– Identification of sources of variability and their impact on product
quality
– Data to be collection based on Risk assessment
• Statistical tools
• Analytical ability for data analysis & meaningful
conclusions
• Team approach
• Presentation of findings
How to improve process
understanding?
Validation - Lifecycle approach
– Stage 1 - Process design
• Defining commercial process based on the knowledge
gained through development & scale-up activities.
• Identifying the sources of variability and establishing
controls (DOE / Risk assessment)
– Stage 2- Process Qualification

• Confirmation of capability of process to result in
reproducible manufacturing (Performance
Qualification)
– Stage 3- Continued Process verification

• Ongoing assurance during routine production that the
process remains in a state of control (Statistical
trending)
20
Desired validated process
Thorough understanding of equipment & process
All variabilities identified and their impact on process and
product quality understood.
All critical process parameters are identified and adequately
controlled
Control strategies based on scientific risk assessment
Operating set points specified instead of ranges along with

process to handle exceptions
Low operator dependence.
Ease of finding the causes in case of failures
Statistical tools
SQC Tools for investigation
• Brain storming
• Five Whys?
• Process flow diagrams
• FMEA
• Cause and Effect Diagram
• Histogram
• Pareto Chart
• Scatter Diagram
• Regression analysis
• Fault tree analysis
• Design of Experiments
• Control Charts
23
Application of SQC tools
Yes DOE
Record Implement NO Test

changes needed More detail process
needed?
changes options
NO
Define Yes
Identify Analyze NO
data to Collect Analyze Need for Improved
probable current C/A? enough?
be data data
causes process
collected
BRAINSTORM PROCESS RECORDS PARETO Yes
CAUSE /
FLOW EFFECT HISTOGRAM SCATTER
5 WHYS?
DIAGRAM DIAGRAM REGRES’n
FTA Record
FMEA Establish regular
unusual
events process monitoring
CONTROL CHARTS
24
Brain storming
Generation of ideas
Involvement of people
Allow people to speak without interruption
Random / sequential
Note down all the ideas without elimination

Five Whys?
• The 5 Whys is a questions-asking method used to
explore the cause/effect relationships underlying a
particular problem.
• Ultimately, the goal of applying the 5 Whys method is to

determine a root cause of a defect or problem.
• Keep asking Why till you reach root cause

Five Why example
Problem : Dissolution failure in tablets
Why it has happened ?
High DT Why is that?
Over lubrication Why is that?
More mixing in Force feeder Why is that?
Slow M/c speed with high feeder RPM Why is that?
Parameters not defined in BMR

Process flow diagram
Helps in Process understanding
Identifies critical steps, critical parameters, control

measures
Helps in identifying probable causes

Fault Tree Analysis
FTA Template
• Graphical representation of the major
faults, the causes for the faults, and
potential counter measures.
• Helps identify areas of concern for

new product design or for
improvement of existing products.
• Helps identify root cause of failure
• Helps identify corrective actions.
• Can be useful both in designing or

investigation.
Cause & Effect Diagram
•Developed by Kaoru Ishikawa Ishikawa / Fishbone Template
•Used to explore potential causes

(6 M’s) that can result in single Measurement
Measurement Methods
Methods Machinery
Machinery
undesirable effect (UDE).
•Potential causes arranged

according to hierarchy UDE
Causes, inputs,
or sources
•Helps in identifying potential of variation
problem areas under each of 6

M’s Manpower Materials Milieu
Manpower Materials Environment
UDE is an Un-Desirable Effect

Failure mode effect analysis
Scientific Risk assessment of process steps
Analyzes each step with respect to its impact on the

quality, probability of occurrence & detectability
Helps in filtering of probable causes

Tools for data analysis
Histogram
Pareto analysis
Scatter plots
Regression analysis
Control charts
X-bar, R, Sigma, Run charts for variables
c, p, np charts for discrete data
Useful for
Process monitoring
Trend analysis of past data
Monitoring effectiveness of CAPA

Data evaluation
Critical information to be reviewed
• Process flow
• Forced degradation study & degradation profile
• Past history
• Material usage / left over stock reconciliation
• Critical process parameters & controls
• Trends of process parameters, process timing, hold time
• Yields
• Machine logs
• Distribution records
• Quality trends, Process capability
• Stability data (exhibit & commercial batches)
• Method validation & transfer data
Assay failures
• Correctness of Formulation
– Label claim / Salt / Water molecule / Batch size
• Correctness of quantities
– Weights / reconciliation of left over / yields
• Working standard
– Response comparison / WS changes / Other batches
• Loss / gain of material
– Yield / water content / physical verification
• Segregation
• Sampling technique
• Sample solution preparation
Failure in RS
– Pathway of formation / Structure / Control measures
• Forced degradation study
• Manufacturing conditions
• Solution stability
– Testing conditions
• Past trend
• Stability data (exhibit / commercial)
• Possibility of contamination
– Testing / manufacturing
DR failures
• Verification of dissolution medium
– pH / Degassing
• Critical component quality
– Release polymers, binders, disintegrants
• Critical process parameters
– Granulation (Power / Current, PSD, BD / TD)
– Mixing (Over lubrication)
– Compression (Speed, force feeder, compaction force)
– Coating (Air flow, inlet temperature, bed temperature, exhaust
temperature, RPM, spray rate, distance of spray gun, left over
solution, weight gain)
– Capsule filling (machine setting, machine principle)
Corrective & Preventive
Actions
What is CAPA?
• CORRECTIVE ACTION
– Action to eliminate the cause of a detected non-conformity or
other undesirable situation
– Corrective action is taken to prevent recurrence of non-
conformity
• PREVENTIVE ACTION
– Action to eliminate the cause of a potential non-conformity or
other undesirable potential situation.
– Preventive action is taken to prevent occurrence of potential
non-conformity
(ISO 9000:2005, ICH Q-10)

Investigation report
What should be included?
• Problem definition
• Discussion on analytical results / observations
• Summary of data reviewed
• Conclusions based on data review
• Experimental plan
• Summary of results of experiments
• Discussion & Conclusion of experiment results
• Final conclusion about root cause
• Corrective & Preventive actions
• Batch disposition
Summary
• Transparency & all time compliance
• Validation as life cycle approach

– Knowledge gain about equipment & process
– Robust process design
• Key skills for investigation

– Domain knowledge
– Analytical ability
– Systematic approach (DMAIC)
– Statistical tools
– Report / Presentation
Control Strategy
In manufacture of Sterile Pharmaceutical/ Drug products.
PHSS ‘White paper’ on principle considerations for a Control Strategy

including additional detail on strategy for contamination control.
Guidelines to create and manage a control strategy in
pharmaceutical manufacturing processes need to be
better defined. This PHSS White paper communicates
principle considerations for a Control Strategy in sterile
pharmaceutical/ drug manufacturing and includes additional
detail on strategy for contamination control.
Introduction
A Control Strategy sets out a documented approach and rationale taken to control product quality,
efficacy and patient safety in manufacture of sterile Pharmaceutical/ Drug products (and substances).
Product quality, efficacy and patient safety can be compromised by contamination as microbiological,
chemical, another product(s) or other biological entities. A control strategy and risk control measures
(technical and organizational) are required in order to help minimise the risks of such compromise.
It is considered Control strategies are increasingly required to support risk based initiatives and new
more complex products and processes to make clear objectives in manufacture of sterile medicines/
pharmaceuticals, biopharmaceuticals, drug products and substances and the approach to control of
manufacturing facilities/ processes, product efficacy/ quality, regulatory compliance and importantly
patient safety.
A Control Strategy should be considered to include: All are inextricably linked.
• Manufacturing control strategy; based on product type, demand, process and risk.
• Quality control strategy; based on understanding of risk with control of Critical
Quality Attributes (CQAs) in a manufacturing process meeting regulatory
requirements.
• Contamination control strategy including cross contamination control that may
include requirements for containment/ product segregation.
The Control Strategy ‘White paper’ has been prepared by a Pharmaceutical and Healthcare Sciences
society - PHSS Bio-contamination special interest who prepared (2014) a monograph (no. 20) on Bio-
contamination related to environmental contamination (airborne and surfaces) in controlled areas/
zones.
The PHSS monograph 20 on Bio-contamination covers the life cycle in microbiological contamination
in controlled areas, with the following topics covered;
• Bio-contamination characterization and risk profiling.
• Control including strategy (based on the White paper), attributes and best
practice.
• Monitoring, including overview of Rapid Micro Methods (RMM).
• Deviation management (investigations, Corrective and Preventative Actions - CAPA.
PHSS definitions relative to the PHSS Bio-contamination monograph and this White paper.
• Bio-burden in a controlled area is microbiological flora, airborne or on surfaces,
pre and post cleaning/ disinfection/ sanitization step. Depending on the
manufacturing stage microbiological bio-burden may be uncharacterised; not
differentiated as isolates or micro-flora.
• Micro-flora is the characterised as ‘‘typical flora’ being typical microbiological
flora found in a classified or controlled area under controlled conditions.
• There should be no typical flora in Grade A controlled areas and
significantly limited flora in Grade B areas. Characterisation includes
identification of microorganisms by groups or isolates (as required)
including genus, species or sub-specifies (as required) and includes whether
organisms are objectionable to products and potentially harmful to
patients. Note: ISO14698 also references the term; micro-flora.
PHSS Control strategy August 2014: V6 –MHRA/IMB reviewed

• Bio-contamination, as environmental microbiological contamination, is detected
contamination in a monitoring program above set levels/ limits and reported
as colony forming units (cfu’s). Alert levels (user set) and action levels (from
regulatory guidance) and adverse trends are studied for deviation together with
determination/ identification of isolates and atypical micro-flora.
• Bio-contamination detected as an adverse trends, where levels of cfu
counts increase above typical levels or the micro-flora profile changes,
indicate a change in control conditions that may not yet have reached
action levels but does warn of increased risk and potential shift towards
loss of control.
• Bio-contamination is a combination of all biological contamination,
including viruses, and related components. Bio-contamination includes
microbiological contamination, endotoxins and pyrogens.
The increasingly complex nature of Pharmaceutical products and interactions between critical quality
attributes, processes, manufacturing environments and patients make the process of assuring
compliance to the three pillars of ‘quality, efficacy and patient safety’ more challenging.
A Control Strategy should be based on a holistic view of all aspects that contribute towards product
quality, efficacy and patient safety. Considerations should include, but not be limited to, product type
and dose form, regulatory requirements, critical quality attributes, manufacturing process, facilities
in manufacturing; including utilities, personnel/ interactions, practice, waste management and any
energy saving management related to control conditions of cleanrooms.
By setting an approach to sterile product manufacturing control in the form of a documented Control
Strategy the objectives are clearly set-out for any given product/ process with principle requirements
established for implementing a risk based approach in product manufacturing.
The Control Strategy should be supported by risk assessments that assist key decisions on how the
product manufacturing control objectives are met with the control steps considered as sequential;
firstly by design (facilities and process), followed by process control and then by procedural control in
operations with reaction to deviations in a well-designed monitoring system.
The Control Strategy should be maintained as a ‘live’ document recognizing building knowledge of
products, process and risk. Holistic considerations and a proactive response to risk escalation should
be inherent in a control strategy.
There should be a recognition that through the process of establishing control leading to a formal
state of control, and approval as a manufacturing process, formal change control will apply where any
change subject to risk/ impact assessment considering risks to quality, efficacy and patient safety.
The Control Strategy should be referenced in a validation master plan (EU GMP Chapter 5 and Annex
15 refer). It should be noted the main principles of the Control Strategy may apply to manufacture of
other non-sterile dose forms where risks to patients need control/ management.

Control Strategy Content
1. Principle components of a Control Strategy
2. Manufacturing Control Strategy
3. Quality Control Strategy
4. Contamination Control Strategy
5. Considerations in setting a Contamination Control Strategy
6. 5.1 Process, infrastructure, operations, components including raw materials.
7. 5.2 Microbial control strategy.
8. 5.3 Risk Management of Contamination (RMC)
9. 5.4 Cross Contamination control/ containment strategy.
10. Summary statement
1.0 Principle components of a Control Strategy

As outlined the Control Strategy should be considered in three component parts all of which are
inextricably linked:
• Manufacturing control strategy.
• Quality control strategy.
• Contamination control strategy.
Manufacturing of sterile Pharmaceutical/ Drug products, substances and constituents requires a risk
based approach, in design; Quality by Design (QbD principles) and in quality under the auspices of a
Pharmaceutical Quality System including Quality Risk Management following ICH Q10 integrated in EU
GMP Part I Chapter 1.
The setting of control strategies in manufacturing combines manufacturing control, quality control
and contamination control to deliver the specified product quality, efficacy and patient safety.
Each aspect of manufacturing, quality and contamination control needs consideration in setting a
Control Strategy. This White paper sets out principle considerations for the Manufacturing and Quality
control strategies with more detail around the Contamination control strategy as the main focus of
this White paper.
2.0 Manufacturing Control Strategy

The Manufacturing control strategy should include considerations on the follow areas together with a
defined approach set out how a specified level of control will be achieved/ implemented:
• Whether the product is to be manufactured by terminal sterilization (preferred
for risk management in patient safety) or by aseptic processing (justified for
product type). For some product types that may be impacted by overkill terminal
sterilization processes it may be possible to justify suboptimal sterilization cycles
that deliver the required Sterility assurance level (SAL) over aseptic processing.

• What is the product type, dose form, quantity required and for what stage of
supply; clinical batches or production batches following Marketing Authorization
(MA).
• Is the manufacturing process by batch, campaign or continuous (with periodic
shut down) and how will change overs be controlled.
• What is the specified process, equipment used and how will process steps be
integrated to form a defined process design/ flow.
• What are the target end points for manufacturing stages.
• What will be the extent of automation required to meet manufacturing control
requirements and how will personnel/ operators interact with the process.
• How will the facility/ utilities and process equipment combine to meet
manufacturing control targets.
• What are the principle risks in product manufacturing that should be subjected to
risk assessment.
• What regulatory of country specific requirements apply to the given product/
process.
3.0 Quality Control Strategy

The Quality Control Strategy should be set around an understanding of the product, process and
critical quality attributes (CQAs) in manufacturing. The control strategy should not be used to try to
mitigate or support bad design or practice.
Risks and impact from deviation in CQAs that provide manufacturing and quality control vary with
the type of product and processing operations/ technologies employed. If the product requires aseptic
manufacturing, is sterile and toxic; or sterile and biological, including non-pathogenic products e.g.
biologicals that use viral vectors but are not a high risk to process operators, different combinations of
product protection, operator protection and cross contamination control are required.
The Quality control strategy should take a holistic view of the life cycle of product manufacture with
control measures at every stage to meet specified objectives, requirements and end points.
It should be recognized that there is a need for a methodical and systematic approach, using risk
management based on products and processes, in setting the control strategy but there will be a need
to keep the document ‘live’.
Due consideration should be given to reassessing the initial design strategy if there is significant
reliance on QC as a form of risk management / mitigation
Product, process and risk knowledge may develop iteratively through process development and a
proactive response will be required as knowledge accumulates during manufacturing implementation
with continuation through the product life cycle.
The focus should always be on product quality, efficacy and patient safety so increasing knowledge
that builds assurance of delivering these critical requirements should be acted on.
It is essential within a Pharmaceutical Quality System (PQS) to control all changes via a change control
process, through all stages of product manufacture. A strategy on how changes are managed should
be included in the Quality Control strategy.

4.0 Contamination Control Strategy
Sterile Pharmaceutical Drug products and substances/ constituents manufactured to GMP need
assurance of quality, sterility or bio burden control (depending on manufacturing stage) and efficacy
that may impact patient safety.
Such assurance that critical quality attributes and patient safety are not compromised by
contamination can only be given by thorough product, process and risk knowledge together with
risk based control aligned with ICHQ9 principles. Control should be implemented through Quality by
Design (QbD principles) and risk control measures defined by risk assessments.
It is well accepted it is not possible to inspect/ test or justify GMP/ CGMP compliance with monitoring
data or media fill results alone as such an approach offers little assurance of robust processes and
assured quality in GMP.
A Contamination control strategy should include a strategy for environmental control of product
manufacturing environments for assurance product sterility is not compromised and patient
safety is not put at risk by loss of microbial control or deviations/ excursions within the controlled
environments.
Strategies in contamination control will vary if the product is aseptically processed/ manufactured,
terminally sterilized, is subjected to sub optimal heat treatment, or a non-sterile ingredient/ constituent
that may require bio-burden control is used.
Relating to the important risks to patients of contamination and cross contamination in product
manufacture it is considered, in accordance with current approaches for Process Validation (PV FDA
2011, EMA draft 2012, EU GMP Annex 15 Glossary, EU GMP Annex 2 point 50), a control strategy
is required based on a holistic consideration and approach to control of all elements that potentially
have an impact on contamination control.
As part of the Contamination control strategy cross contamination should be considered as there
may be risks of cross contamination by chemical adulteration/ residues between processes, product to
product cross contamination, biological entities cross contamination and cross contamination between
patients via cells/ genes if manufacturing is for therapy products.
5.0 Considerations in setting a Contamination Control

Strategy:
The following is a more detailed listing of what should be assessed when setting a Contamination
control strategy based on a holistic view across:
5.1: Process, infrastructure, operations, components including raw materials.

• Facilities, equipment and Barrier technologies.
• Process; control measures and monitoring with deviation management.
• Qualifications, process, equipment and personnel that impact contamination
control.
• Personal and operations.
• Components including raw materials and waste management.

5.2: Microbial control strategy.
• Microbial Control targets in classified and controlled areas.
• Microbial contamination risks and proactive response to risk escalation.
• Decontamination processes and monitoring to verify control.
• Critical control points and contamination control attributes.
5.3: Risk Management of Contamination (RMC).

• Based on PHSS Monograph 14: RMC – adapted HACCP method.
• Seven steps in Risk Management of Contamination.
• RMC register: Contamination source, control measures, sampling plan.
5.4: Cross Contamination control/ containment strategy.

• Closed system processing and use of single use systems.
• Cross contamination control attributes.
• Containment/ segregation strategies to prevent cross contamination.
• Decontamination between different product manufacturing/ processing.
5.1 Facility infrastructure, process, equipment, operations,

qualifications and components including raw materials.
5.10: Facilities, equipment and barrier technologies

• The methodology in contamination/ cross contamination control should be
reflected in the facility and process design to meet requirements for specified
products or processes.
• Facilities; including utilities, facility layout, equipment, materials, personnel flows,
specification of controlled areas should be considered e.g. zoning; EU Grade
A/B/C/D or ISO classes and requirements for restricted personnel access.
• The Contamination control strategy should include a listing/ statement of
contamination control attributes including physical attributes relating to controlled
environments used for product manufacture e.g. facility zoning, HVAC systems
used to control air quality, pressure differentials and control of temperature plus
(as required) humidity.
• Sterilisation technologies used for product contact parts and critical surfaces that
impact product sterility should be defined.
• Equipment used in process and/or in contamination control should be defined.

• Barrier Separation Technology employed e.g. Isolators or RABS: Restricted Access
Barrier Systems, should be defined. If a RABS barrier separation technology is
specified a statement and justification is required defining if the barrier is an Open
Operation RABS (open barrier door - operator access during processing) or Closed
Operation RABS (best practice – no open door access in process) Definitions from
PHSS RABS Monograph 15.
5.11 Process; control measures and monitoring with deviation management

• The rationale for selection of sterilization, disinfection/ sanitization and cleaning
technologies/ methods and associated regimes should be considered including the
combination/ interaction for a given process.
• Process controls for contamination and cross contamination control should be
defined.
• Monitoring systems that provide detectability and early warning of deviation
in critical quality attributes and/or critical control parameters that impact
environmental control and/or product sterility. Where applicable, Process Analytical
Technology (PAT) should be used to enable ‘real time’ monitoring of processes and
environments.
5.12 Qualifications, process, equipment and personnel that impact

contamination control
• Strategy for Process Qualification (PQ), Re-Qualification (RQ) and continuous
verification of contamination control performance (cross referenced to Validation
Master Plan; VMP).
• Qualification of procedural controls, SOPs (Standard Operating Procedures)
in process operations and at critical operator interactions with a process or
products to verify there is no compromise to the manufacturing environment and
potentially product quality/ sterility. The emphasis here is on critical qualification
activities e.g. sterilisation, disinfection, environmental control measures, utilities
etc. with media process simulations/ media fills used as an assessment of in-place
controls.
• Strategies for deviation investigations should include a strategy for Root cause
analysis to determine the root or most probable cause followed by corrective
and preventative actions (CAPA) and related efficacy checks to verify corrections/
changes.
5.13 Personnel and operations

• Control of personnel in the facility and controlled areas in respect to
contamination control and prevention of contamination transfer e.g. personnel
numbers, training, procedures (SOPs), gowning system, gowning practice,
gowning qualifications.
• Training of personnel that have process/ product interactions is an iterative process
e.g. in procedures (SOPs), practice, aseptic technique and qualifications including
finger dabs, gown monitoring, ongoing assessment and associated qualifications
through media process simulations/ media fills, trending of data and analysis of
those trends.
• Control strategy for preventative and corrective maintenance to assure there is no
compromise to contamination control status or assurance of product sterility.

5.14 Components/ equipment, raw materials and waste management.
• Control of components including equipment, raw materials, excipients, APIs,
container/ closure items and change parts etc. in supply, quality (including sterility
or bioburden if applicable) and transfer into controlled zones for use in a specified
process.
• Control of all consumable/ single use materials in entry to controlled areas of
a higher grade/ class via airlocks, pass-trough’s that include a disinfection step
to prevent contamination transfer and compromise of contamination control
status in receipt zone; For EM plates use of irradiated media where applicable to
the zone. Procedural control using multiple wrapped items with step wise layer
removal at each transfer may apply.
• Control of cleaning/ sanitization/ disinfection materials on entry/ exit from
controlled areas together with use/ storage where there is potential impact on
contamination control status.
• Control of waste, reject materials from a process that may impact contamination
status of the controlled areas or cross contamination to other controlled areas.
5.2 Microbial control strategy for environmental control

The microbial contamination control strategy should cover all aspects of establishing microbiological
control in controlled and classified areas/ zones, to defined regulatory limits/ levels with trending of
data and appropriate routine analysis to verify a formal state of control where deviations above action
levels or repeated frequencies above alert levels in key locations require investigation and correction to
prevent reoccurrence. Using trend analysis data may also facilitate a proactive response to prevent a
bio-contamination event by an intervention to cease increasing micro flora that may be developing to
unacceptable numbers of counts.
It is recommended in the control strategy that a key performance indicators (KPIs) are developed using
a holistic review of environmental monitoring data to determine the points of contamination risk
escalation but ensuring the KPIs do not normalise the data to such an extent trends are not visible.
Environmental monitoring at targeted risk/ control points in facilities including key interfaces of;
personnel transfer, interactions and process/ material transfers provide an opportunity to detect
increased contamination transfer to adjacent zones or controlled areas.
Adverse environmental monitoring trends which may include increasing cfu counts or a changes in
micro-flora profile (qualitative and quantitative data) at zone to zone interfaces may provide an early
warning in manufacturing stages that the critical manufacturing environments, processes and sterile
products are at increased risk of contamination.
As risks escalate and adverse trends become evident, even before excursions above ‘’not to exceed’’
regulatory limits/ levels of colony forming unit (cfu) microbiological contamination or atypical micro-
flora is detected in the controlled areas, appropriate proactive responses can be taken to avoid
contamination that may impact critical manufacturing environments and sterile products.
Contamination outside regulatory limits/ levels often leads to complex root cause investigations. It
may be difficult to ascertain the source/ root cause in a deviation event or trend shift and therefore
challenged in providing specific effective corrective and preventative measures and also difficult
assessing how much product or batches may be impacted.

It is better to manage contamination of critical areas and or sterile products by measures of avoidance
with an early warning proactive strategy rather than reactive strategy to deviation events.
Using holistic environmental monitoring data: zone to zone comparisons of pressure differentials, total
particulate and viable counts/ micro-flora can facilitate a proactive response to adverse trends/ events.
Strategies of how such holistic data is collected, analysed and acted on needs defining in the control
strategy.
Considerations for the Microbial control strategy should include:
• Zoning of controlled areas by classification EU GMP A, B, C, and D and/or ISO
classes.
• Flow of the process, products, materials and personnel and their interactions.
• Environmental control, including airflow, air-changes, clean-up times and pressure
differential cascades/ regimes.
• Cleaning, disinfection/ sanitization programs: selection and qualification of
cleaning/ disinfection products used, their target efficacy and the application using
defined techniques. Regimes that use multiple disinfection agents in rotation
should be stated and justified.
• Cleaning and disinfection procedures (SOPs) and associated qualifications.
• Control points for material transfer between controlled/ classified areas/ zones
which may be different depending on the technology used – examples as follows;
• Penetrative (porous load) decontamination/ sterilisation using moist heat.
• Transfer devices with semi or automated disinfection control steps including
Gaseous Disinfection GD-VHP surface bio-decontamination processes.
• Non chemical surface sterilizers e.g. e-beam/ bio-decontamination devices
e.g. UV.
• Transfer hatches with manual disinfection control steps
• Material transfer control points and disinfection/ decontamination methods
should be appropriate/ compatible for materials in transfer with target material
surface bio-decontamination efficacy stated and justified for the specified transfer
method/ device.
• Change room control points for contamination control during personnel access to
controlled/ classified areas/ zones.
• Monitoring systems that provide ongoing (event and trend) information on
status of contamination control via monitoring alert and action levels of microbial
contamination and associated total particulate levels (via continuous monitoring
in critical areas) should be considered. Due consideration should also be given to
facility (unclassified) monitoring where deemed necessary in order to determine
the potential risks placed upon the environmental controls within the classified
cleanrooms. Monitoring systems should be routinely assessed for effectiveness and
open to change and improvement.

• Rapid Micro Methods (RMM) that provide real time environmental monitoring
microbial data that are not growth based hence intervention free to sampling
points may offer advantages in proactive response strategies and risk reduction
without the need to enter growth media plates into critical areas. Such
technologies, in development, need careful evaluation in data analysis (generated
bio-counts not cfu’s) and comparability studies to classical growth based
environmental monitoring methods.
5.3 Risk management of Contamination (RMC)

The PHSS Monograph 14 provides guidance on Risk Management of Contamination (RMC) during
manufacturing operations in Cleanrooms and controlled air devices.
The RMC approach to cleanroom contamination control has been adapted from the Hazard Analysis
of Critical Control Points; HACCP method and provides an effective system to manage the risk from the
various sources of microbial contamination during cleanroom manufacturing.
It consists of the following seven stages;
1. Identification of the sources of contamination and routes of transfer to the product including
assessment of the process and existing control measures; should involve observational
assessment.
2. Assessment of the risk from the sources and routes of contamination and, where appropriate,
remove the source of risk or introduce risk mitigation; introduce new control measures, or
improve existing control measures, to reduce risk.
3. Establishment of a monitoring schedule using valid sampling methods to monitor the hazards,
or their control methods, or both. Establishment of alert and action levels with corrective/
preventative action procedures to be followed, when these levels are exceeded.
4. Verification, on a scheduled basis, that the contamination control system is appropriate
by reviewing the product contamination rate, the environmental monitoring results, the
risk assessment and control methods and the action levels, and where appropriate, modify
accordingly.
5. Establishment and maintenance of appropriate documentation.
6. Training of the personnel.
7. Determine the microbial risk to the patient from the product.
The risk assessment stage is usually the most difficult stage to undertake but is a major component in
the overall risk management process, and calculates the level of risk associated with a contamination
source that should be controlled.
Accurate assessment is critical, and indicates where effort and resource should be best applied.
An assessment based upon the fundamental method of contamination transfer will provide the most
accurate method as it utilizes the actual contamination process.
This approach is therefore appropriate for aseptic manufacturing processes and is used for the risk
assessment stage.

A documented register should be prepared of each contamination source, the contamination control
methods and the monitoring methods at risk based sampling locations together with sampling
frequency and assigning action/alert levels. The outcome should be to remove identified risks where
possible, mitigate against others and lastly utilization of monitoring methods as a mechanism of
assessment of those risk control strategies.
5.4 Cross contamination/ containment control strategy

Cross contamination may be in the form of chemical (including toxic), biological, product or patient
to patient biological entities (cells, genes etc.). Microorganisms are not considered in the strategy
for cross contamination control unless they are process generated and cross contamination between
processes is a process risk requiring control.
Containment may be required for biological materials including live entities, toxic or cytotoxic products
as powder or liquid form, products at molecular or nano-scale and operator sensitizing products.
Consideration of national environmental health and safety at work legislation is appropriate given the
risks to human health from potential cross contaminating toxic or highly potent chemical or biological
residues.
Product segregation may be required by facility, controlled areas and containment equipment
depending on the toxicological profile of the products.
The Control strategy should be supported by risk assessments to define segregation requirements
related to hazards, risks and contamination/ cross contamination control requirements.
The Cross contamination control strategy should define the risks and approach to management of
cross contamination that may include a requirement for containment. Containment may be localized,
by equipment/ closed systems, or in combination with facility design or by temporal segregation, e.g.
campaign running.
Considerations in a cross contamination control strategy should include both technical and
organizational measures such as:
• Use of closed processing technologies/ equipment and single use systems
(disposable).
• Validated decontamination steps between processes, equipment and product
manufacturing stages.
• Use of containment barriers e.g. Isolators that provide containment boundaries
suitable for product containment and decontamination including cleaning in place
technologies and safe-change HEPA filter systems.
• Airflow and pressure differential schemes based on containment principles.
• Management of all contaminated waste from cleaning and processing.
• Monitoring of working behavior to ensure training effectiveness and compliance
with the relevant procedural controls.
• When all other possibilities have been discounted, the use of dedicated facilities.

6.0 Summary statement
With increasing complexity in product manufacture, interactions between ‘Open and Closed’
processing systems, interactions between automated processes and manual operations/ interventions a
control strategy provides an important focus on approach taken in control.
Key characteristics of a control strategy for contamination control would be considered as:
• Product and process knowledge together skills in pharmaceutical product
manufacturing and GMP/ cGMP compliance critical to an effective risk based
approach to control.
• Under the auspices of a Pharmaceutical Quality System (PQS) together with
initiatives of Quality by Design (QbD) and Quality Risk Management (QRM).
• All changes as a result of increasing knowledge, process improvements are subject
to a change control process.
• Dynamic and iterative throughout the product life cycle.
• Holistic and proactive.
• Based on targeted/ risk based measures of contamination avoidance
• Uses key performance indicators (KPIs) to assess status of contamination control
• Includes a defined strategy for deviation management: investigations and CAPA.
Acknowledgements
This White paper was prepared by the PHSS Bio-contamination special interest group. The information
and guidance in the PHSS White paper on Control Strategy for manufacture of Sterile Pharmaceutical
products is a consensus view of the PHSS special interest group and does not necessarily represent
the views of individual’s affiliations or host companies, acknowledged in the PHSS Bio-contamination
monograph 20.

epr314 drinkwater_Layout 1 25/06/2014 08:46 Page 1
IN-DEPTH FOCUS: MICROBIOLOGY
© kurhan / Shutterstock.com
James L. Drinkwater
Chairman of Pharmaceutical and
Healthcare Sciences Society and
Leader of a PHSS Bio-contamination
Special Interest Group
Risk Profiling and Proactive

Response (RPPR) to
Bio-contamination in GMP
classified and controlled areas
This paper introduces an initiative based on microbiological risk profiling and a proactive response to bio-
contamination risk escalation in classified and controlled environments. The concept is included in the PHSS
Bio-contamination monograph 201. The monograph considers four principle requirements of a systematic approach
to bio-contamination risk management and a microbial control strategy with guidance on best practice (see
Figure 1, 0pposite); risk profiling is one key area where a systematic approach could yield significant benefits.
Characterisation and profiling of microorganisms in classified areas group is used to proactively respond to risk escalation in contamination
during establishing control when base lines and ‘library’ isolates are of Grade A critical areas. Proactive response is an intervention before a
established is an accepted practice in all facilities to provide reference contamination event or excursion outside defined regulatory limits or
data for environmental monitoring programmes and investigations. trend levels occurs. There are clear benefits to utilising the RPPR
Today with improved data management systems, microbiological initiative in the manufacture of aseptic products, in reduction or
characterisation data can be analysed as profiles and used in operation elimination of difficult and expensive bio-contamination root cause
to monitor area to area relationships and yield a holistic overview of investigations plus improved patient safety.
contamination control. Holistic operational data provides early warning
of possible loss in contamination control status providing a chance to Bio-contamination Risk Profiling and
be proactive in response. The PHSS initiative is called risk profiling and Proactive Response (RPPR)
proactive response (RPPR). Incidence rates and microbiological flora by The premise of RPPR is that bio-contamination tracks through a facility,
38 European Pharmaceutical Review VOLUME 19 ISSUE 3 2014

area to area, transferred via people, air movements and on

material surfaces, and any resulting increase in contamination
levels in one area increases the risk to contaminating another,
then possibly resulting in contamination of the critical Grade A
zones (see Figure 2, page 40) which in turn may lead to product
contamination. On this premise it follows that unless there are
control points that are an absolute barrier in transfer of bio-
contamination to Grade A zones, it is just a matter of time before
Keeping Your Quality under Control
a critical contamination event occurs if there are adverse trend
changes in microbiological levels and flora in supporting areas. In
reality, no barrier operated as a manufacturing system with Microsart®@media
complex interfaces, human interactions can provide an ‘absolute’
control to microbiological transfer. Grade A areas are unlikely to be
sterile, so risks are present that must be understood and
managed. In the past, bio-contamination transfer by tracking
through a facility has become evident when external construction
activities or seasonal changes increase risks and recovery in
contaminations events.
Critical zone contamination events are followed by difficult
root cause investigations with potentially inconclusive findings.
To improve risk management, there is a need to move to a
proactive initiative avoiding a purely reactive approach when
Grade A areas are compromised.
Figure 1: PHSS Bio-contamination Monograph Structure
As it cannot be assumed that a Grade A environment inside an

isolator or restricted access barrier system (RABS)2 will be a barrier
to (and free of all) bio-contamination transfer from the surround
or at material transfers, then reducing the microbiological
challenge and variability has to be the focus. Although there is a
significant risk reduction with the use of barrier separation
technology (BST) in support of quality by design (QbD), it is clear
that other risk mitigation control measures are required.
The fact that a number of EM samples can be recorded as
zero (0) cfu as part of an environmental monitoring program in
Grade A / ISO5 classified areas in compliance to GMP annex 13/
FDA Guidance to industry for aseptic processing4 does not mean
bio-contamination is not present, because they only represent a
small sample at defined locations and typically only at a certain
point in time.
Well characterised real-time rapid microbial methods (RMMs)
using fluorescence based measurement technologies with high
sensitivity in recording environmental bio-counts enhances
sampling with non-intervention technology at high-risk locations
but the surroundings may be still open to undetected con-
tamination providing an elevated risk factor. RMM real time
www.sartorius.com/microsart
VOLUME 19 ISSUE 3 2014 European Pharmaceutical Review
environmental monitoring systems do facilitate a

responsive real time action as a result of detected
deviations in critical Grade A locations e.g. produc-
tion hold preventing exposure of remaining batch to
risk, but If we now change the focus to holistic
monitoring for risk escalation such RMM technology
could also be put to good use in Grade C areas.
Bio-contamination presence and risks are not
entirely evident with use of existing classical
monitoring techniques as there is an inability to
detect all microorganisms via environmental
monitoring (EM) programs. Classical growth based EM
techniques and methods historically have poor
recovery, cannot detect viable but non-culturable
(VBNC) microorganisms and have limitations in Figure 2: Bio-contamination Risk profiling & characterisation
sampling that provide only a snapshot of con -
tamination control status with retrospective results. It is recognised more detail species level or genomic identifications
Monitoring the holistic profile – including the Grade C/B areas are required as part of root cause investigations into contamination
– provides measurable microbiological levels so changes in profile, events but the state of control as a trend can be adequately
cfu levels and microflora can be detected and analysed as trends. represented by flora group types typically as periodic, campaign and
If the focus remains on monitoring Grade A areas without linking seasonal ‘pie or control charts’.
changes in contamination levels in support areas, then available The relative percentage change of one microbiological group to
data that could be analysed holistically to improve knowledge about another will shift inherently through transition of establishing control
the performance of contamination control in facility/process operation into a control state. Thereafter there may be seasonal changes or as a
is not made use of, and will not give such a complete understanding result of other influences, possibly changes related to external facility
of the risks. activities. Once ‘expected’ microflora is understood in the control state,
then deviation from the characterised and expected flora; by cfu levels,
Bio-contamination risk profiling and characterisation incidence rates and group type, can be defined as a risk escalation to
There are two parts to bio-contamination risk profiling across contaminating Grade A facilitating a proactive response.
combined areas: The microbiological monitoring profile groups defined in the PHSS
n Bio-contamination levels measured as cfu ranges Bio-contamination Monograph are:
(see Figure 3, page 41) with incidences of deviations from n Bacilli
regulatory limits reported as percentages of total EM samples n Gram negative rods (related to endotoxin risks)
in a trended EM programme n Human commensals
n Microbiological profiles characterised as ‘expected’ and n Moulds and yeasts
atypical flora. n Others; including environmental non-sporing rods
n Defined; atypical microorganisms.
The definitions of objectionable microorganisms (that may also be
harmful to patients) are more appropriate to sterile and non-sterile For some time, the regulatory authorities have been challenging both
products and not necessarily environments where atypical as a the industry and those involved in GMP to take a more holistic approach
deviation from the expected would seem more relevant to promote an to contamination control because individual events or episodes only
investigation of what’s changed. If a microorganism is objectionable to form part of the picture in contamination control and risks to patients.
a product, the control measures in the facility should eliminate the risk One MHRA inspector commented to the PHSS: “If only the company
of transfer to critical environments and product. Such objectionable would have looked at the data they had holistically it was obvious a
microorganisms, if detected in an EM programme, would be reported as contamination event in Grade A was going to happen.”
atypical but the impact and risk significance would be higher. In addition, others who have had Grade A contamination events,
Objectionable microorganisms may include gram negative now aware of the RPPR initiative, have gone back to examine the EM
bacterium that leads to endotoxin risks (causing fever in patients who data holistically across all supporting areas and found evidence of an
may also be immunologically compromised) and are of particular increasing risk of a contamination event in Grade A, that could perhaps
concern for biological product manufacturing, e.g. monoclonal have been prevented by an early intervention.
antibodies, that may have challenges in endotoxin detection as a result Accepting the limitations in environmental monitoring, limita-
of ‘masking’ effects. tions in media fills to provide absolute assurance of continuity
It is impractical to characterise every microorganism in a facility or in contamination control through production operations and
controlled area for trend monitoring, so a more realistic approach is to limitations of sterility testing (end point testing) that is scientific-
monitor profile changes in defined groups of microbiological flora. ally and statistically challenged, the focus has to be on preventing

contamination and not monitoring for compliance in con -

tamination control.
It follows that if the focus on monitoring facilities remains
completely reactive to bio-contamination events, this leads to
difficult investigations and corrective and preventative actions
(CAPAs), often with loss of product batches in the process. Loss of
product batches is not just a high financial penalty but also puts
into question the quality in manufacturing and control leading to
increasing regulatory scrutiny and potential patient risk due
MICROBIAL
CONTAMINATION?
to compromised supply of medicines.
In risk management of processes, practices and procedures,
operating within process environments where the Grade A critical
areas have exposed products at the highest risk of contamina- We can help find the root cause.
tion, the initiatives of quality by design (QbD) and quality
risk management (QRM) 5 must be part of the strategy and Microbial excursions. They have the ability to shut down
rationale for bio-contamination control. The RPPR initiative production, delay product release and instigate lengthy
adds to risk management by using existing tools, techniques and root cause analysis — all while you wait days for critical
data but with improved data management and analysis together active air sampling data.
with a change in focus towards considering risk escalation and Stop waiting. The BioTrak® Real-time Viable Particle
proactive interventions preventing occurrence of critical Counter from TSI provides immediate notification of
contamination events. microbial contamination by utilizing validated* Laser
The risks of Grade A bio-contamination in a well-designed and Induced Fluorescence (LIF) optical spectroscopy to
analyze each particle, resulting in real-time viable
managed facility are mitigated but there are always challenges
measurements — and benefits.
from a variety of bio-contamination sources transferred from
people (gowned operators), environments (airborne) and facility / + Instantly begin root-cause analysis with time-
material or component surfaces. With good facility and process
stamped viable particle count data
design, it is less likely (but still possible) for contamination via + Quickly assess and release cleanrooms following
direct Grade A interfaces, e.g. heating, ventilation and air
decontamination
conditioning (HVAC) with associated HEPA filtration deficiencies or + Integrated particle collection filter for offline analysis
of optically analyzed particles
issues in contamination from other direct utility or process
support inputs. Don’t wait to improve your process.
Start now with a higher caliber of data.
Understand more at tsi.com/biotrak-9510
Figure 3: Representation of not to exceed cfu counts on

EM growth media plates
Process and product (WFI) water quality will always need

special attention regarding contamination control measures and
monitoring. As environmental bio-contamination can track
through the facility, bio-burden control and reduction at each
transition in classified areas is a key part of controlling the risk
escalation to contaminating Grade A environments.
A proactive response to bio-contamination risk escalation
may include a controlled/documented intervention during
operations to prevent risk of a contamination event or improved
process/facility design to provide enhanced contamination
UNDERSTANDING, ACCELERATED
VOLUME 19 ISSUE 3 2014 European Pharmaceutical Review
* Type V Drug Master File (DMF) #028184

control performance. There is an important contamination risk Determining ‘expected’ flora could be difficult, but once established
reduction by restricting or eliminating operator interventions where then the holistic profile and deviation from the characterised
there is risk of exposure to critical areas, surfaces or sterile product. In expected profile in microbiological flora becomes a key performance
addition contamination control can be improved with more effective or indicator (KPI).
automated disinfection/ sanitisation and bio-burden reduction on
material surfaces during transfers between zones. Summary
The PHSS Bio-contamination Special Interest Group believe that, together
with QbD and QRM initiatives, this systematic control and holistic risk
profiling and proactive response (RPPR) initiative will make a significant
contribution to bio-contamination control and risk management.
Understanding and control of critical quality attributes (CQA) and
monitoring for deviation is a key requirement in risk management
within Grade A areas, but now we need to understand the impact and
contamination risks from downstream facilities and processes.
By taking a holistic view of measurable environmental monitoring data
outside of Grade A areas, we can detect risk escalation before bio-
contamination events occur in Grade A areas.
Implementing the RPPR initiative will not be without challenges but
the benefits are clear and support regulatory expectation in delivering
risk management with improved patient safety, particularly for
Figure 4: Barrier ‘shell’ concept in GMP. *PCCA = pharmaceutically controlled aseptically prepared products where bio-contamination has a
clean areas. *BFS = Blow Fill Seal
potentially high product impact and increased patient risk.
The EU GMP annex 1 and cGMP FDA guidance to industry for aseptic Having introduced here the RPPR concept which is discussed in
processing have been defined not to exceed microbiological detail in the PHSS Bio-contamination Monograph 20; the next
contamination limits/levels with the key support areas of Grade B / ISO consideration will be the impact of this holistic based bio-
7 and Grade C / ISO8 in operation specified with measurable data (cfu contamination risk management initiative on the revision to GMP Annex
levels) that can be used to build a holistic bio-contamination profile 1 and re-write of ISO 14698: Bio-contamination of surfaces and airborne.
(area to area).
For improved contamination control on an holistic basis, there may Acknowledgements
be a need to improve disinfection/sanitisation in the key Grade C / ISO 8 The PHSS wish to acknowledge the expertise provided by contributors
area as this is a critical control point in a GMP facility using the shell-like to the bio-contamination monograph and the RPPR initiative. The
(see Figure 4) barrier concept with increasing cleanliness (classified area guidance in the monograph is a consensus from the special interest
to area) at progression through a facility to the critical Grade A area(s). group and does not necessarily represent the consensus of view from
Adopting the holistic risk profiling model, recognising Grade C is a host companies or organisations. A listing of Bio-contamination Special
critical facility control point, will lead to an increase in monitoring in Interest Group members, including regulatory authority review is
Grade C areas and associated interfaces. included in the monograph.
To characterise the ‘expected’ microbiological flora in Grade C areas
and detect deviation that results in risk escalation to bio- References
1. Pharmaceutical the Healthcare Sciences Society – PHSS Bio-contamination monograph
contamination in Grade A will not be without its challenges, but, when 20: April 2014. www.phss.co.uk
in place, will significantly enhance risk knowledge and management and 2. PHSS Restricted Access Barrier Systems – RABS Monograph 15. 2011
3. EudraLex ‘The Rules Governing Medicinal Products in the European Union’ Volume 4
sterility assurance levels in critical areas. ‘EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and
Challenges of characterising a microbiological profile as ‘expected’ Veterinary Use Annex 1
4. FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing —
with increased monitoring in Grade C areas will include the following: Current Good Manufacturing Practice. 2004
n There will need to be an increase in environmental monitoring 5. EU GMP Annex 20 – Quality Risk Management – QRM. For reasons of coherence and
completeness, the ICH Q9 guideline has been transferred completely into GMP Annex 20
(EM) resource
n Grade C areas are not aseptically controlled in the same way as
As Head of Aseptic processing technologies and GMP
Grade A or B so there is more variation of flora Compliance at F Ziel Germany, James Drinkwater is
n Water may be present involved in Barrier technology projects, Isolators, RABS,
Material transfer chambers in applications of production and
n By necessity, equipment operates that is not fully enclosed
clinical trial scale Filling, Aseptic processing, ATMPs, IMPs
or sterilised and Sterility/ product testing. In addition to the role at F Ziel,
n Non-sterile materials are handled James has a voluntary role as Chairman of the not-for-profit
society, PHSS – Pharmaceutical and Healthcare Sciences Society and
n A higher number of operators are present compared to
Leader of the PHSS Bio-contamination and RABS Special Interest Groups,
Grade B rooms plus he is a member of the UK mirror group re-writing the standard ISO
n Given the above, the micro-flora is continuously changing in 14698 on bio-contamination (surfaces and airborne). James is a member of
the PDA and ISPE.
numbers and species.

Is Indian industry over designing the
Aseptic Manufacturing Plants it builds ?
PHSS India ISIG 2014 Conference series ; Mumbai & Goa, November 2014
PHSS Presentation 2: 11:15 am – 12:15 pm
Is Indian industry over designing

the Aseptic Manufacturing Plants it builds ?
NNE Pharmaplan Consultant
formerly Head
of the French GMP Inspections

Senior Technology Partner, NNE PHARMAPLAN
GMP Compliance Manager SNC Lavalin Pharma
International Auditor, CICR (The Red Cross)
GMP Consultant, (NNE) Pharmaplan
Head of the GMP inspection, the French Agency
GMP Consultant, Pharmaplan
Quality Assurance Director, Ipsen
Quality General Manager, Janssen-Cilag (J&J)
GMP inspector, the French Agency
Production Manager, Pharmygiene (Omega)
Dr J-D Mallet
Quality Assurance Manager, Janssen (J&J)
Jdma@nnepharmaplan.com Technical Assistant, Roussel-Diamant Maroc
Pharmacist, MBA

I performed about 500 inspections or audits since 1994
of which some 42 were in India of which 17 in sterile facilities

Agenda

(from 1963 to 2014)

(a comparison)


(some FDA findings)

Agenda

(from 1963 to 2014)

(a comparison)


(some FDA findings)

1963 : the very first cGMP issued in the USA few words
1969 : the WHO GMPs are published few paragraphs

1971 : revision of the (FDA’s) cGMP 21CFR210-211
1971 : first publication of the Orange guide* (UK) first real annex for steriles
1975 : revision of the WHO GMP guide
1976 : 21CFR212 draft for parenteral products never published in the FR
1978 : second revision of the 21CFR210-211 (current)

1987 : first FDA aseptic processing guidance first aseptic guidance
1989 : PIC/S* & EU-GMP guide first published contains annex 1 for steriles
1994 : FDA guide to inspection of sterile APIs
1996 : first revision of the EU-GMP annex 1
2002 : first Indian GMP published in the Gazette contains an annex for steriles
2004 : revised FDA aseptic processing guidance a very detailed document (50p)
2006 : Japanese guidance on aseptic processing a 100+ page document
2008 : last revision of the EU-GMP annex 1 under revision again ?

The first cGMP regulations were issued by Geo. P. Larrick,
Commissioner of Food and Drugs (FDA) one year after the
Kefauver enactment, on June 20, 1963, in the Federal Register
Pyrogen free
sterile
products
premises
8 columns in the FR

few paragraphs (6)
terminal
sterilization
aseptic
processing
monitoring
4.2

few paragraphs (con’t)
equipment
checks
premises
layout
laminar
air-flow
techniques

1971
a 10-page document not requiring MFT (revised in 1974)
1975
a general WHO document mentioning the MFT for validation
1976 a very specialized document addressing the

manufacturing conditions for terminally sterilized SVPs
and LVPs – it has never been published as a guide
1978 a general document that has been

amended at several occasions but which
is still the compendial FDA cGMP guide
1987 FDA guide (40 pages)

on sterile products
produced by aseptic
processing – containing
new detailed requirements
which underlined the
concept of critical areas

1989 Annex 1 to the EU-GMP similar to the
Annex 1 to the PH 5/89 guide of PIC/S which
itself has been inspired from the Orange guide
successive annexes (1971, 1974,1977 & 1983)
1996 A major revision of the Annex 1 to the EU-GMP

introducing the concept of grade A continuity
2001 Revision of two points (MFT and gowning)
2003 Revision of the 5µ particle counts
in the classification table (one, not zero)
2008 This revised version of the
Annex 1 for sterile products has
been re-arranged and includes
four important changes :
- 5µ particle counts revised
- new provisions for MFT
- precisions on bioburden
- increased environmental
requirements for capping seals
This annex has now 15 pages of
requirements (few explanations
are given on the contrary of
some other Int’l guidances

Agenda

(from 1963 to 2014)

(a comparison)


(some FDA findings)

2002 2004
16 pages 50 pages
Sterilized Aseptic
Aseptic
2008 2011
15 pages 110 pages
Sterilized Aseptic
Aseptic

Table 1 : comparison of environment classification
2002 2004 2008 2011

16 pages 50 pages 15 pages 110 pages
Terminal & Aseptic Aseptic Terminal & Aseptic Aseptic

4 grades 4 grades 4 grades 4 grades
A, B, C & D ISO 5, 6, 7 & 8 A, B, C & D A(5), B(7), C(8) & D
0,5 µ particles 0,5 µ particles 0,5 µ particles 0,5 µ particles
5,0 µ particles --- 5,0 µ particles 5,0 µ particles
At Rest & In Op. In Operation At Rest & In Op. At Rest & In Op.

3500 (0,5) / 0 (5) 3520 (0,5) 3520 (0,5) / 20 (5) 3520 (0,5) / 20 (5)

< 1cfu/m3) 1cfu/m3 < 1cfu/m3 < 1cfu/m3
It should be noted here that the revised schedule M states for 29 particles in A but 293 in B

Table 2 : comparison of microbiological grades
2002 2004 2008 2011

Air sampling Air sampling Air sampling Air sampling
Settle plates Settle plates (opt.) Settle plates Settle plates
--- --- Surfaces Surfaces
Fingers Fingers Fingers Fingers
A <1 cfu/m3 ISO 5 1 cfu/m3 A <1 cfu/m3 A <1 cfu/m3
B 10 cfu/m3 ISO 6 7 cfu/m3 B 10 cfu/m3 B 10 cfu/m3
C 100 cfu/m3 ISO 7 10 cfu/m3 C 100 cfu/m3 C 100 cfu/m3
D 500 cfu/m3 ISO 8 100 cfu/m3 D 200 cfu/m3 D 200 cfu/m3
A <1 / plate ISO 5 1 / plate A <1 / plate A <1 / plate
B 5 / plate ISO 6 3 / plate B 5 / plate B 5 / plate
C 50 / plate ISO 7 5 / plate C 50 / plate C 50 / plate
D 100 / plate ISO 8 50 / plate D 100 / plate D 100 / plate
Pl. Time exposure Plate time exposure Plate tilme exposure Plate time exposure
minimum 2 hours 4 hours 4 hours 4 hours
and 30 minutes in A

Table 3 : comparison of engineering basics

Manufacturing Separate rooms
“Direct support
and support depending on
Clearly stated Clearly stated area“ and “indirect
areas separation operations but
support area“
not so explicit
Smooth internal Rounded floor
surfaces and Non explicit for Non explicit for the
Clearly stated & accessible
coves the coving coving
corners
Airlocks and Final stage of

Black Focus on the
changing rooms the same grade Separate rooms
Grey entry/exit
(at rest) that the for entry and exit
White process
final area
Drains Prohibited in Prohibited in Prohibited in A/B
Only in ISO 8
Class A & B Class A & B Conditions for C
Aseptic handling
A in B ISO 5 in 6 or 7 A in B A in B
conditions

Table 4 : comparison of HVAC basics
Clean up time 30 minutes not specified 15-20 minutes 15-20 minutes
Not specified Minimum 30 in

Air Change Per Minimum 20 for Typically 20 for
(was 20 in old Grade B and
Hour Grade B and C Class ISO 8
versions) minimum 20 in C
Air velocity in 0,45 m/s (hor.)

0,45 m/s 0,45 m/s 0,45 m/s
laminar airflows 0,30 m/s (ver.)
Delta-P 10-15 Pa
At least At least
between two 15 Pa at least (guidance
10-15 Pa 10 to 15 Pa
classes (pascals) value)
HEPA integrity Twice a year At least once a

Yearly Not specified
testing (DOP) (for aseptic) year

Table 5 : comparison of basics instructions
Sterilized
At each work At each work Should not be
garments Gown change
session session reused
(aseptic)
Sterilized or
Sanitized Sterilized
Goggles Not mentioned desinfected
goggles goggles
goggles
Product filter Optional before

Immediately Before and after
integrity routinely after Not specified
after use use
verification use
Supervision of Intercom From outside the Windows or

Not explicit
operations telephones clean area video cameras
Temperature Should not Should be

Temperature < 27°C
and humidity interfere with the compatible
and humidity <55% RH
controls standard and controlle

Figure 1 : situation resulting from a poor engineering
Free cables*
Shedding
elbow
Door open*
Agenda

(from 1963 to 2014)

(a comparison)


(some FDA findings)

Orange Guide, 1971 (the ancestor – 4 pages)
Orange Guide, 1974 (first revision – 8 pages)
Orange Guide, 1977 (second revision – 9 pages)
Orange Guide, 1983 (third revision – 15 pages)
EU-GMP Guide, 1992 (initial release ; no % for MFT)
EU-GMP Guide, 1996 (first revision ; MFT 0,1%)
EU-GMP Guide, 2001 (revision § 42 ; MFT twice a year)
EU-GMP Guide, 2003 (2nd revision ; one five µ particule in A)
EU-GMP Guide, 2008 (current version ; MFT target zero growth)

Aseptic processes or significant

modifications should be validated by using
a sterile nutrient medium for simulating
the process to be performed. That
validation should be repeated at defined
intervals (Annex 1, § 38).

Validation of aseptic processing should include simulating the process

using a nutrient medium. The form of the nutrient medium used should
generally be equivalent to the dosage form of the product. The process
simulation test should imitate, as closely as possible the routine aseptic
manufacturing process and include all the critical subsequent
manufacturing steps. Process simulation should be repeated at defined
intervals and after any significant modification to the equipment and
process. The number of containers used for a medium fill should be
sufficient to enable a valid evaluation. For small batches, the number of
containers for the medium fill should at least equal the size of the
product batch. The contamination rate should be less than 0.1% with
95% confidence level (Annex 1, § 42).

Validation of aseptic processing should include a process simulation test using a

nutrient medium (media fill). Selection of the nutrient medium should be made based
on dosage form of the product and selectivity, clarity, concentration and suitability for
sterilisation of the nutrient medium. The process simulation test should imitate as
closely as possible the routine aseptic manufacturing process and include all the
citical subsequent manufacturing steps. It should also take into account various
interventions known to occur during normal production as well as worst case
situations. Process simulation tests should be performed as initial validation with three
consecutive satisfactory simulation tests per shift and repeated at defined intervals
and after any significant modification to the HVAC-system, equipment, process and
number of shifts. Normally process simulation tests should be repeated twice a year
per shift and process. The number of containers used for media fills should be
sufficient to enable a valid evaluation. For small batches, the number of containers for
media fills should at least equal the size of the product batch. The target should be
zero growth but a contamination rate of less than 0.1% with 95% confidence limit is
acceptable. The manufacturer should establish alert and action limits. Any
contamination should be investigated (Annex 1, § 42).

Validation of aseptic processing should include a process simulation test using a nutrient medium (media
fill). Selection of the nutrient medium should be made based on dosage form of the product and selectivity,
clarity, concentration and suitability for sterilisation of the nutrient medium.
The process simulation test should imitate as closely as possible the routine aseptic manufacturing process
and include all the critical subsequent manufacturing steps. It should also take into account various
interventions known to occur during normal production as well as worst-case situations.
Process simulation tests should be performed as initial validation with three consecutive satisfactory
simulation tests per shift and repeated at defined intervals and after any significant modification to the
HVAC-system, equipment, process and number of shifts. Normally process simulation tests should be
repeated twice a year per shift and process.
The number of containers used for media fills should be sufficient to enable a valid evaluation. For small
batches, the number of containers for media fills should at least equal the size of the product batch. The
target should be zero growth and the following should apply:
When filling fewer than 5000 units, no contaminated units should be detected. When filling 5,000 to 10,000
units : One contaminated unit should result in an investigation, including consideration of a repeat
media fill ; Two contaminated units are considered cause for revalidation, following investigation.
When filling more than 10,000 units : One contaminated unit should result in an investigation;
Two contaminated units are considered cause for revalidation, following investigation.
For any run size, intermittent incidents of microbial contamination may be indicative of low-level
contamination that should be investigated. Investigation of gross failures should include the potential impact
on the sterility assurance of batches manufactured since the last successful media fill (Annex 1, § 66-70).

Annex 1 : from 1992 to 2008 (sixteen years of improvements)
289
Number
of words
contained 6800
in annex 1 205 205
+50% 6100
122 5800
5700
10 folds
4600
49
the
Annex 1 number
of words
29
for MFT
1992 1996 2001 2003 2008

EU-GMP
Annex 1
eudralex vol.4
(Dec.2009
published
Completed with
Feb.2008
PIC/S PI032-1 )
re-published
Nov.2008 INTERPRETATION OF
MOST IMPORTANT
coming into force CHANGES FOR THE
in March 2009 MANUFACTURE OF
STERILE MEDICINAL
and March 2010*
PRODUCTS
+ PIC/S PI032-2
(January 2010)

EU-GMP
Annex 1 story

EU-GMP
Annex 1 story
And now ?

EUROPEAN GMP Guideline Story : it continues !
What has to be
discussed now is
“how big” is the
updating need :
a) clarification
Grade A air supplies
b) revision
e.g. new technologies
c) re-writing
e.g. missing forms
d) harmonization

Agenda

(from 1963 to 2014)

(a comparison)


(some FDA findings)

While the EMA has started now to post non-compliance reports
on its eudragmp website, the US-FDA website is by far the
place where you can get the richest information :

Most of the failings identified by the FDA or the European
inspectors are related with poor or even bad practices that are
not directly linked with the premises or the equipment :
Your firm has not established or followed the appropriate written

procedures designed to prevent microbiological contamination of
drug products purporting to be sterile. For example, approximately
846 environmental monitoring (EM) samples were not collected
in the Class 100 (Grade A) and the Class 10,000 (Grade C) areas
from March 2010 to February 2012 during the manufacture of
sterile injectable products … [320-13-03]
Operators working inside the aseptic core were observed wearing

goggles that had not been adequately sterilized and had two
openings on the top. The goggles currently worn in the Class 100
area are not sterilized but rather sanitized …. [320-13-03]

Your firm failed to establish an adequate system for monitoring

environmental conditions in aseptic processing areas in that the
inspectors found that you do not have a scientific justification for
alternating the use of sampling by settle plates and swabs
and we are concerned that you may have underestimated the
number and type of bacterial species that are present on the
two different geloses you use because you have no data to
support the equivalent sensitivity and efficiency of bacterial
recovery on these supports … [320-14-15]
We note that your firm prepares the media plates used for EM
sampling at your site. Prior to using them, you pre-incubate the
plates and we are concerned that this practice may compromise the
media’s growth promotion potential. Provide evidence to demonstrate
that pre-incubation of the media plates does not adversely impact the
ability to promote microbial growth… [320-15-003]

You have have not performed smoke studies under dynamic

conditions to ensure that unidirectional airflow protects the
product during aseptic filling operations. In your response, you
indicate that you are making arrangements to perform dynamic
smoke studies. However, your response fails to provide any
justification that the aseptic processing line has proper airflow
Our investigators observed poor aseptic practices that increase
the risk to product sterility assurance. For example, operators
with exposed skin were observed making interventions over
open product using a non-sterile forceps.
Our investigators observed inadequate gowning of operators
who routinely reused gowning throughout the day to enter
the sterile core for set-up and filling… [320-14-07]

Your firm failed to maintain the buildings used in the

manufacture, processing, packing, or holding of a drug product
in a clean and sanitary condition and keep them free of
infestation by rodents, birds, insects, and other vermin :
a. during the inspection of the facilities, investigators noted
significant mold growth in the washroom located at the entry to
the sterile manufacturing area […]
b. the investigators noted numerous dead insects in the
“Sample Pass Through” Room, located approximately […] from
the small volume parenterals sterile filling line… [320-14-13]

Table 6 : inspection findings and engineering
Engineering
WL Finding Correction
impact (ex.)
EM sampling missed Ancillary area

320-13-03
Non sterilized goggle Table top sterilizer
Two different methods in Ancillary area

320-14-15 alternance – 2 geloses Laboratory
Pre-incubation of the
320-15-03 Probably no impact
environmental plates
No smoke studies
Line refurbishing
320-14-07 Exposed skin
Airlock refreshing
Gowning reused
Mold growth HVAC refreshing

320-14-13
Dead insects Additional rooms

Remember !
3 5

Agenda

(from 1963 to 2014)

(a comparison)


(some FDA findings)

Figure 2 : an ideal facility ?

Figure 3 : continuous improvement is a must
Milieu
Methods
Men
Materials
Machines
EU-GMP 1996 revision

A full knowledge and understanding of the process
PAL storage
MAL
X
personnel rooms
material post
airlock(s)
airlock(s) processing
rooms
washing
IPC Core room
Core room
room(s)
rooms
sterilization
preparation
room(s)
room(s)

A good definition of the ventilation needs
Grade Air
Which operation(s)
(Class) Changes
A Critical +600
& use of systems
B No operation 60 where necessary
X
C Non critical 30
D Preparation 20
E No operation 12
(CNC)
F Circulation 6
This table only reflects the personal opinion of the author on the topic

A full control of entries and exits
ingress
filtered AIR C personnel

F H
personnel I E products
C
materials L K waste
T Core room -
V
fluids & gases
E A
equipment
L
consumables R V (drains)
S E
equipment S extracted AIR
leaks

A perfect control* of all exposed surfaces
X
lights
doors
walls windows
pipes
covings equipment
grids
floors
* Controlled means : cleanable, smooth, inert, resistant, non electrostatic, etc.

A plain layout with successive clean areas
E/B B/C C/D
COMPONENT FILLING (A) PACKAGING (D)

HANDLING (B)
D/B
PACKAGING MAT.
PREPARATION (D)
NON CRITICAL OPERATIONS (C)
E/D E/D E/C C/D D/E E/D E/D
CORRIDOR (E)

What is the cost of an ideal facility ?
Costs of design flaw(s) :
depending on the time
where such failure(s)
Is(are) identified … 1 if identified during consultancy
10 if identified during conceptual
100 if identified during basics
if identified
1000 during detailed
maybe 100 crores if identified by inspectors

Thank you very much
Jean-Denis Mallet
Any
Docteurquestion
en pharmacie ?
Is it possible to over play aseptic operations ?

to me, the answer is clearly “no you can’t”

Please remember…
when processing aseptically,

the devil is in the details

Thank you all again
Jean-Denis Mallet
for inviting me in Goa
Docteur en pharmacie
NNE PHARMAPLAN

PHSS I-SIG Technical Confere

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PHSS I-SIG Technical Confere

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INDIA PHSS I-SIG Conference 2014

Welcome & Introduction

Acceptable Quality & Patient Safety

Chapters 1 Chapters 2 Chapters 3 Chapters 4

PHSS conference at Courtyard Marriot Mumbai November 19, 2014

o Why changing regulatory scenario across the globe has to

o New regulatory requirements are brought almost

o In India also, the new drug approval process has

o -In 2013 only 23 new drugs were approved,

o Following are the major areas where regulatory

 QbD (Quality by Design)

Though QbD has put considerable

 USFDA -new guidance for generic development :

• Guidance on size & shape of tables & capsules

• US FDA introduced GDUFA - on 1st October 2012,

 Starting material (SM) characterization, source, carryover of

 If SM is too complex, reviewer is asking to redefine it & go few

 Reviewers are strictly applying ICH Q 3A & Q3C to limit impurities

 Limits of genotoxic alerts – TTC approach or based on relevant

 Implementation of ICH Q-3D -- Elemental impurities has already

 More focus has come on cross contamination

 For highly potent products containment is

 Anti counterfeit measures :

• USFDA passed DSCSA in 2013. Effective 1st Jan 2015, the

 Child resistant packs

 Different Approach is taken by different regulators-

 For some locally acting oral products , US ask for

 For Ophthalmics – US FDA is giving prior clearance on

 Dose proportionality concept followed by US FDA &

 No. of audits by regulators have gone up

 No. of import alerts & warning letters issued by USFDA

 Majority of the observations were related to practices,

 In recent months, USFDA has identified more than dozen

 As global player, we have to comply with variation guidance

 TGA revised variation guidance last year

 WHO – Variation guidance amendment in 2013 & 14.

 Beginning Oct 1st , 2014, USFDA has applied GDUFA goals to

 All major regulators have actively implemented

- USFDA has brought out REMS requirement for

- EU has already brought restricted use for drugs like

 Manufacturing facilities ,CROs - √

 BE, clinical end point studies - √

 Regulatory compliance – we need to bring more focus through positive

 We need to be ever prepared for regulatory audits !

 Post- approval changes, Life-cycle management- √

 Pharmacovigilance, drug safety - √

Control Strategy for Contamination and

• Is control strategy something new?

• It has been integrated into GMP for a long time via

– ICH Q8; Q9; Q10.

A control strategy is designed to ensure a product of required

• Q10 control strategy has been integrated into Chapter 1 (31st

1.2 lifecycle stages from the manufacture of investigational

• This is a logical scientific approach that can readily form part

Hasn’t Chapter 5 always had control measures?:

• Measures to prevent cross-contamination and their

• Processes and procedures should undergo periodic critical

• 3 aspects of a control strategy:

For an effective control you have to consider all three

• Understand the product and processes and write them down

• What are the critical process parameters

• For sterile products the issues are

 they have to be manufactured consistently

• Therefore contamination/cross contamination control is