ISPE Tampa Conference

22-25 February 2010

Tampa, Florida USA

FDA Perspective on Multi-Product Facilities,

Risk-Based Approach to Containment of Highly
Hazardous Compounds

ISPE Tampa Conference

Containment Technology Forum
February 25, 2010

Edwin Melendez
Consumer Safety Officer
Center Drug Evaluation and Research
Office of Compliance
Div. Manufacturing and Product Quality 1

Agenda
Cross Contamination
Source / Define / Concerns
Compounds
Hazardous & Not-So Hazardous
Regulatory Perspective for Compounds
Regulations / Guidance / Policy
Risk-Based Approach to Containment of Hazardous Compounds
Identify Hazardous Compound
Factors Affecting Potential for Exposure
Causes for Cross-Contamination
Beta-Lactam Containment Control Program
Potent Compound Risk Assessment (Logic diagram)

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Cross Contamination
Sources of Contaminants
Filth
dirt, debris, pest, product residue, lubricating oils, etc.
Microbiological
bacteria, fungi
viruses: biotech products (mammalian cell culture)
Toxins
infectious agents (spore-formers)
endotoxin (gram negative bacteria debris)
aflatoxins (fungal/mold metabolites)
Poisons (toxic non-pharmaceuticals)
pesticides, herbicides, etc.
Compounds (hazardous & not-so hazardous)
Beta-Lactam Antibiotics - Sensitizing Substances
Potent Compounds (High Pharmacological Activity)
All other drugs
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Cross Contamination

Contamination of a material or product with another

material or product. ICH Q7A, GMP Guidance for APIs

Any substance accidentally or unknowingly

introduced into/onto a product (possibly rendering it
harmful).

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Cross Contamination
Concerns

Toxic reaction may not be apparent to a health

professional treating patient (non-intentioned usage)
It may be impossible to trace to product contamination
Contaminants introduced are difficult to detect (e.g.,
penicillin contamination in cephalosporin)

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Compounds
APIs & Finished Products

Beta
Beta-Lactam
Lactam Antibiotics (highly sensitizing)
Penicillins
Non-penicillins beta-lactams
Potent compounds: [for example: OEL 10g/m ]
Cytotoxics
Steroids
Hormones
Many others with different pharmacological activity

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Compounds
Approved Beta-Lactam Product Categories

Penicillins (~23)
Cephalosporins (~31)
Penems (~3)
CarbaCephem (1)
Monobactams (1)

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Compounds
Potent Compounds (industry perspective)

Biological activity < 15grams/kg human weight

[Or therapeutic dose at or below 1 milligram]
Compound with a potential to cause cancer, mutation,
developmental effects, or reproductive toxicity at low
levels
Compound with OEL 10 gms/m
gms/m/8hr/shift
/8hr/shift
A novel compound of unknown potency & toxicity

SafeBridge Consultants, Inc., Mountain View, CA, Naumann,B.D.et al, Performance-based,

American Industrial Hygiene Journal, 57:33-42, 1996
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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Compounds
Hazard Continuum
Occupational Exposure Limit (OEL)

>1,000 g/m3 1,000 g/m3 100 g/m3 10 g/m3 1 g/m3 <1 g/m3

>10,000 g/day 10,000 g/day 1,000 g/day 100 g/day 10 g/day <10 g/day

Acceptable Daily Intake (ADI)

Potency
Less Severe More Severe

ISPE WashDC Conference, Containment Tech Forum, 6/6-7/07

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Compounds
Potency classification scheme, generic (3)

Category 1 Category 2 Category 3 Category 4

Occupational
Exposure limit >500 500 - 10 10 - 0.1 <0.1
(g/m)

Toxicity and Low Moderate Potent Highly

Potency potent

Source: SafeBridge Consultants Joe Carey, PharmaceutcalTechnology DrugDelivery2008,

Pages s34-s38

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22-25 February 2010
Tampa, Florida USA

Regulatory Perspective
Regulations Specific to Penicillin (PCN) Drugs

21 CFR 211.42(d)
Separation of facility and equipment

21 CFR 211.46(d)
Separate air handling systems (HVAC)
21 CFR 211.176
Test non-PCN drugs g for traces of PCN where possible exposure exits. Do
not market if detectable levels are found.
Test according to Procedures for Detecting & Measuring Penicillin
Contamination in Drugs [Codified Test Method]

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Regulatory Perspective
Regulatory Citation for Non-Penicillin Beta ()-Lactams

There shall be separate or defined areas or such other control

systems for the firms separation as are necessary to prevent
contamination [211.42 (c)]
-Lactam contamination of any other drugs
(e.g., cephalosporin contaminants in aspirin tablets)
-lactam contamination in other -lactams
(e.g.,
(e g cephalosporin contaminants in carbapenem)

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22-25 February 2010
Tampa, Florida USA

Regulatory Perspective
GMP Guidance for APIs

Statutory Requirement [FD&C, Sec.501(a)(2)(B)]

all drugs and APIs must be manufactured in conformity with CGMPs

Q7 GMP Guidance for APIs, section IV.D. Containment (4.4)

Dedicated production areas should be employed in the production of
highly sensitizing materials, such as penicillins or cephalosporins.

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Regulatory Perspective
Summary - Sensitizing -Lactams

The CGMPs specifically require separation of penicillin

production.

For similar reasons, we also expect non-penicillin -

lactam drugs to be produced in separate MFG facilities
from other drug products.

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Regulatory Perspective
Regulatory Citation for Potent Drugs

There shall be separate or defined areas or such other control

systems for the firms separation as are necessary to prevent
contamination or mixups [211.42 (c)]
Manufacturers should assess all drugs handled in non-dedicated areas and
establish defined areas or controls necessary to prevent the risk of product
cross-contamination . [Case-By-Case Basis]
All compounds are potent, some are more potent than others.
Process evaluated in our CGMP inspections
Review supporting data & analyses for firms product introduction decision

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Regulatory Perspective
APIs - Toxic (potent) Substances

Q7 GMP Guidance for APIs, section IV.D Containment

(4.41)
Materials of an infectious nature or high pharmacological activity to toxicity

... dedicated production areas should... be considered unless validated

inactivation and/or cleaning procedures are established and maintained
maintained.

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Regulatory Perspective
Summary - Potent Compounds and all other drugs

Manufacturers are to decide what level of controls are

necessary to prevent the potential for cross-contamination.

Some drugs such as certain cytotoxics, steroids,

hormones and other highly potent drugs may require
extraordinaryy controls over manufacturing g because of their
greater potential for toxicity, unintended therapeutic effect,
or cross-sensitization.

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Risk-Based Approach to Containment of

Hazardous Compounds
(Beta-Lactams or Potent Compounds)

Identify Hazardous Compound (nature of hazard)

Factors Affecting Potential for Exposure (manage risk
by controlling exposure)
Knowledge of the Causes for Cross-Contamination
Beta-Lactam Containment Control Program
Potent Compound Risk Assessment (Logic diagram)

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Factors Affecting Potential for Exposure

[Material exposure increases risk of cross-contamination]
Wet Physical Form Dry
Large Particle Size Small
Dense Density Light
Closed Operation Open
No Energy / Velocity Process High Energy/ Velocity
None Required Operator Skill Highly Dependent
Low p Pressure High p
None Transfers Multiple
Well Training Poorly
Well Maintenance Poorly
Routine Task Type Non Routine
One Operation Frequency Multiple Operation

As presented to FDA by ISPE Jan2006 19

E.Melendez2.10/ISPE.Tampa

Causes for Cross Contamination

Mechanical Transfer
Operators/materials/equipment alternating between 2 or more processes or areas
Operators clothing & Non-product contact surfaces
Airborne Transfer (open operations, spills, leakage)
Uncontrolled release of dust, gases, vapors, sprays from materials and products in
process
Migration of airborne particles thru-out facility
Equipment Residues
Multi-use: residues from prior production activity
Dedicated: degradation (build-up & lack of cleaning)
Mix-Up
Inadequate design of facilities and equipment
Inadequate procedural controls
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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Beta-Lactam Containment Controls

Circumstances under which a containment

control/monitoring program would apply
Beta-Lactam operations in a Multi-product manufacturing facility
(building or campus)

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Containment Controls
Containment Monitoring Program

Objective:
Demonstrate Containment of Beta-Lactam Compound

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Containment Controls
What
Wh t are FDA expectations
t ti f an adequate
for d t containment
t i t control
t l/
monitoring program for beta-lactam compounds?
Plan:
Representative Sampling Plan
Containment control procedures
Analytical procedures and surface sampling techniques
Product testing
g ((when there is a reasonable p
possibility
y of contamination))

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Warning Letter: -Lactam (paraphrased)

International Major Generic Manufacturer
Failure to adequately establish separate or defined areas for the mfr. &
processing of non-penicillin beta-lactam products to prevent contamination
or mix-ups [211.42(c)]. Operations related to the manufacturing of
penicillins are not adequately separated from non-penicillin products
[211.42(d)].
During the inspection, our investigators observed inadequate containment
practices regarding the handling and movement of personnel, equipment, and
materials as follows:
Examples causes for cross-contamination
cross contamination
Your containment control and monitoring programs are inadequate to prevent
cross contamination of non-penicillin pharmaceutical products (APIs & finished
dosage forms) with possible residues of penicillin, cephalosporin, or penem
compounds as follows:
Examples lack or inadequate containment procedures & testing

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Potent Compound Risk Assessment

MFRs should assess all drugs handled in non-dedicated

areas and establish defined areas or controls necessary
to reduce the risk of product cross-contamination. [Case-
By-Case Basis]
Process evaluated in our CGMP inspections
Review supporting data & analyses for firms product introduction
decision
Logic diagram
Adapted from an ISPE, presentation at Wash., DC, on 14th Nov.,
2007 by Paul Wreglesworth

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1 Is there a specific requirement to handle the

product in a dedicated facility?
Has the requirement been imposed by a
regulatory agency?

Has the requirement been imposed internally?

g a risk assessment has the level of risk

Following
been deemed unacceptable?

Are there operational reasons for separating this

product from others?
Adapted from ISPE presentation 11/14/07PWreglesworth 26

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Logic diagram to assist with Manufacturing and Sourcing decisions

- cGMP/Regulatory focus

COMPOUND X GMP/REGULATORY LOGIC

NO
1 Is there a specific requirement to handle the product in a dedicated facility? YES

obtain cleaning validation criteria

NO

can cleaning demonstrably

be carried out to meet
NO
the required criteria?
feasibility
cost can the cleaning criteria be met
practicability
for some of the stages?

YES
can the contaminated
equipment be isolated to
YES NO
prevent cross-contamination of
are there any other factors other part of plant/facility?
that could prevent the use
of a multi-product plant?
YES can these
facility standards
operational
issues be resolved?

YES
YES NO
NO

can be accommodated in can be accommodated in multi-product facility with dedicated equipment or units can only be
multi-product facility accommodated in
with no restrictions OPTIONS single product class facility

disposable
dedicated dedicated unit
equipment for
equipment for (in multi-product Adapted from ISPE presentation 11/14/07PWreglesworth
a given process
a process step facility)
step

SINGLE OR MULTI-PRODUCT PLANT CHOICES

27
ASSET ACCOMMODATION DECISION

2 Obtain appropriate criteria to support

cleaning
Knowledge
g of Material
Toxicity Properties (the nature of the hazard)
Solubility
Cleanability
Degradation Products
Cleaning Agents
Microbiological Contamination (if applicable)
Establishment of Limits
Practical
P ti l
Achievable
Verifiable
Safe
Justified
Adapted from ISPE presentation 11/14/07PWreglesworth 28
E.Melendez2.10/ISPE.Tampa

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Logic diagram to assist with Manufacturing and Sourcing decisions

- cGMP/Regulatory focus

COMPOUND X GMP/REGULATORY LOGIC

NO Is there a specific requirement to handle the product in a dedicated facility? YES

obtain cleaning validation criteria

2
NO

can cleaning demonstrably

be carried out to meet
NO
the required criteria?
feasibility
cost can the cleaning criteria be met
practicability
for some of the stages?

YES
can the contaminated
equipment be isolated to
YES NO
prevent cross-contamination of
are there any other factors other part of plant/facility?
that could prevent the use
of a multi-product plant?
YES can these
facility standards
operational
issues be resolved?

YES
YES NO
NO

can be accommodated in can be accommodated in multi-product facility with dedicated equipment or units can only be
multi-product facility accommodated in
with no restrictions OPTIONS single product class facility

disposable
dedicated dedicated unit
equipment for
equipment for (in multi-product Adapted from ISPE presentation 11/14/07PWreglesworth
a given process
a process step facility)
step

SINGLE OR MULTI-PRODUCT PLANT CHOICES

29
ASSET ACCOMMODATION DECISION

Can cleaning be carried out to

3
meet the required criteria?

Feasibility
what is the requirement?
contact parts vs. non-contact parts
Cost
Is the cost reasonable?
Practicability
time to clean
need to recover or segregate rinse waters

Adapted from ISPE presentation 11/14/07PWreglesworth 30

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Logic diagram to assist with Manufacturing and Sourcing decisions

- cGMP/Regulatory focus

COMPOUND X GMP/REGULATORY LOGIC

NO Is there a specific requirement to handle the product in a dedicated facility? YES

obtain cleaning validation criteria

NO

3 can cleaning demonstrably

be carried out to meet
the required criteria?
NO
feasibility
cost can the cleaning criteria be met
practicability
for some of the stages?

YES
can the contaminated
equipment be isolated to
YES NO
prevent cross-contamination of
are there any other factors other part of plant/facility?
that could prevent the use
of a multi-product plant?
YES can these
facility standards
operational
issues be resolved?

YES
YES NO
NO

can be accommodated in can be accommodated in multi-product facility with dedicated equipment or units can only be
multi-product facility accommodated in
with no restrictions OPTIONS single product class facility

disposable
dedicated dedicated unit
equipment for
equipment for (in multi-product Adapted from ISPE presentation 11/14/07PWreglesworth
a given process
a process step facility)
step

SINGLE OR MULTI-PRODUCT PLANT CHOICES

31
ASSET ACCOMMODATION DECISION

Can the criteria be met for

4 some stages of the process?
Dedicated or disposable equipment parts
Cleaning standards for dedicated or disposable parts
Storage requirements for dedicated parts
Cost of dedication for low volume products
Impact of segregation on plant services

What if part of the

equipment train proves
impossible to clean? [Yes]

Adapted from ISPE presentation 11/14/07PWreglesworth

32

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Logic diagram to assist with Manufacturing and Sourcing decisions

- cGMP/Regulatory focus

COMPOUND X GMP/REGULATORY LOGIC

NO Is there a specific requirement to handle the product in a dedicated facility? YES

obtain cleaning validation criteria

NO

can cleaning demonstrably

be carried out to meet
the required criteria?
feasibility
cost
NO
4 can the cleaning criteria be met
practicability
for some of the stages?

YES
can the contaminated
equipment be isolated to
YES NO
prevent cross-contamination of
are there any other factors other part of plant/facility?
that could prevent the use
of a multi-product plant?
YES can these
facility standards
operational
issues be resolved?

YES
YES NO
NO

can be accommodated in can be accommodated in multi-product facility with dedicated equipment or units can only be
multi-product facility accommodated in
with no restrictions OPTIONS single product class facility

disposable
dedicated dedicated unit
equipment for
equipment for (in multi-product Adapted from ISPE presentation 11/14/07PWreglesworth
a given process
a process step facility)
step

SINGLE OR MULTI-PRODUCT PLANT CHOICES

33
ASSET ACCOMMODATION DECISION

5 Can contaminated equipment be isolated to prevent cross-

contamination of other parts of the plant / facility?

Isolate in-situ
Contained equipment?
Dedicate Suites?
Remove and store in isolation
Residue cleanup?
Contained storage area requirements?

Adapted from ISPE presentation 11/14/07PWreglesworth 34

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Logic diagram to assist with Manufacturing and Sourcing decisions

- cGMP/Regulatory focus

COMPOUND X GMP/REGULATORY LOGIC

NO
Is there a specific requirement to handle the product in a dedicated facility? YES

obtain cleaning validation criteria

NO

can cleaning demonstrably

be carried out to meet
NO
the required criteria?
feasibility
cost can the cleaning criteria be met
practicability
for some of the stages?

YES
5 can the contaminated
equipment be isolated to
YES NO
prevent cross-contamination of
are there any other factors other part of plant/facility?
that could prevent the use
of a multi-product plant?
YES can these
facility standards
operational
issues be resolved?

YES
YES NO
NO

can be accommodated in can be accommodated in multi-product facility with dedicated equipment or units can only be
multi-product facility accommodated in
with no restrictions OPTIONS single product class facility

disposable
dedicated dedicated unit Adapted from ISPE presentation 11/14/07PWreglesworth
equipment for
equipment for (in multi-product
a given process
a process step facility)
step

SINGLE OR MULTI-PRODUCT PLANT CHOICES

35
ASSET ACCOMMODATION DECISION

Are there any other factors that could

6 prevent the use of multi-product facilities?

Common handling
g or change
g areas
Cross contamination in dispensaries charging/discharge
areas
Surface contamination on clothing.
Previous Facility History (Internal and CMOs)
What knowledge of other products handled in the proposed
facility (currently and historically)?
Will a CMO choose not to handle certain product classes?
What risk assessments will be required?

Adapted from ISPE presentation 11/14/07PWreglesworth 36

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Logic diagram to assist with Manufacturing and Sourcing decisions

- cGMP/Regulatory focus

COMPOUND X GMP/REGULATORY LOGIC

NO Is there a specific requirement to handle the product in a dedicated facility? YES

obtain cleaning validation criteria

NO

can cleaning demonstrably

be carried out to meet
NO
the required criteria?
feasibility
cost can the cleaning criteria be met
practicability
for some of the stages?

YES
can the contaminated

6
equipment be isolated to
YES NO
prevent cross-contamination of
are there any other factors other part of plant/facility?
that could prevent the use
of a multi-product plant?
YES can these
facility standards
operational
issues be resolved?

YES
YES NO
NO

can be accommodated in can be accommodated in multi-product facility with dedicated equipment or units can only be
multi-product facility accommodated in
with no restrictions OPTIONS single product class facility

disposable
dedicated dedicated unit
equipment for
equipment for (in multi-product Adapted from ISPE presentation 11/14/07PWreglesworth
a given process
a process step facility)
step

SINGLE OR MULTI-PRODUCT PLANT CHOICES

37
ASSET ACCOMMODATION DECISION

Logic diagram to assist with Manufacturing and Sourcing decisions

- cGMP/Regulatory focus

COMPOUND X GMP/REGULATORY LOGIC

NO Is there a specific requirement to handle the product in a dedicated facility? YES

obtain cleaning validation criteria

NO

can cleaning demonstrably

be carried out to meet
NO
the required criteria?
feasibility
cost can the cleaning criteria be met
practicability
for some of the stages?

YES
can the contaminated
equipment be isolated to
YES NO
prevent cross-contamination of
are there any other factors
that could prevent the use
of a multi-product plant?
7 can these
other part of plant/facility?

facility standards YES

operational
issues be resolved?

YES
YES NO
NO

can be accommodated in can be accommodated in multi-product facility with dedicated equipment or units can only be
multi-product facility accommodated in
with no restrictions OPTIONS single product class facility

disposable
dedicated dedicated unit Adapted from ISPE presentation 11/14/07PWreglesworth
equipment for
equipment for (in multi-product
a given process
a process step facility)
step

SINGLE OR MULTI-PRODUCT PLANT CHOICES

38
ASSET ACCOMMODATION DECISION

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22-25 February 2010
Tampa, Florida USA

8 Flexible Options

Multi-product facility with adaptation for

specific products/processes:
Dedicated or disposable equipment.
Dedicated suites or units.
Containment and/or segregation systems.

Adapted from ISPE presentation 11/14/07PWreglesworth 39

Logic diagram to assist with Manufacturing and Sourcing decisions

- cGMP/Regulatory focus

COMPOUND X GMP/REGULATORY LOGIC

NO Is there a specific requirement to handle the product in a dedicated facility? YES

obtain cleaning validation criteria

NO

can cleaning demonstrably

be carried out to meet
NO
the required criteria?
feasibility
cost can the cleaning criteria be met
practicability
for some of the stages?

YES
can the contaminated
equipment be isolated to
YES NO
prevent cross-contamination of
are there any other factors other part of plant/facility?
that could prevent the use
of a multi-product plant?
YES can these
facility standards
operational
issues be resolved?

YES
YES NO

8
NO

can be accommodated in can be accommodated in multi-product facility with dedicated equipment or units can only be
multi-product facility accommodated in
with no restrictions OPTIONS single product class facility

disposable
dedicated dedicated unit
equipment for
equipment for (in multi-product Adapted from ISPE presentation 11/14/07PWreglesworth
a given process
a process step facility)
step

SINGLE OR MULTI-PRODUCT PLANT CHOICES

40
ASSET ACCOMMODATION DECISION

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 ISPE Tampa Conference
22-25 February 2010
Tampa, Florida USA

Warning Letter: Potent Compound (paraphrased)

Domestic Contract Mfg. Operation

L
Lack
k off a consistent
i t t approachh for
f classifying
l if i d
drugs iin tterms off th
their
i
cross-contamination risk; and, establishing defined areas or controls
necessary to prevent cross contamination. For example:
Knowledge of an APIs hazards including potential for loss of containment .
Risk associated with product contact and/or non-product contact surfaces.
Process properties for APIs and finished product.
Product exposure to the manufacturing environment occurs during what points in
the process
Facilitys design characteristics regarding flow of operations and HVAC systems
Analytical methodology for environmental and product testing for possible
contamination.

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Warning Letter: Potent Compound (paraphrased)

Domestic CMO

Inadequately
q y designed
g controls both p
procedural & p
process
leading to inefficiency & unwarranted confidence:
Vessels used in the mfg. of potent compounds exit the filling area
through the aseptic gowning room, capping room, and entry room prior
to cleaning.
Failure to have written SOP that identify drugs with risk and establish
defined areas or controls necessary to reduce risk of product cross-
contamination.
Failure to keep records for the maintenance
maintenance, cleaning , and sanitizing of
equipment.
Failure to adequately validate cleaning procedures for equipment used
in MFG. and packaging operations of drug products.

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Tampa, Florida USA

Thank you
10903 New Hampshire Ave
Bldg. 51, Rm. 4370
Silver Spring, MD, 20993

Edwin Melendez
Consumer Safety Officer
Division of Manufacturing & Product Quality
Office of Compliance
Center for Dr
Drug gE
Evaluation
al ation and Research

Phone: 301-796-3284 Fax: 301-847-8741

E-mail: edwin.melendez@fda.hhs.gov

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