Download Bioburden Control of Non-sterile Drug Substances and Products

USP <1115> Bioburden Control of Non‐sterile Drug Substances and Products: Intent Implementation
Products: Intent, Implementation and Impact
Tony Cundell, Ph. D.
Consulting Microbiologist
Consulting Microbiologist
Scarsdale, NY
August 4, 2014
IVT Microbiology Week
1
Disclosures
• The
The opinions expressed in this presentation opinions expressed in this presentation
are solely mine and not those of my former employer Merck & Co the USP Microbiology
employer Merck & Co, the USP Microbiology Committee of Experts or my current consulting clients
consulting clients.
August 4, 2014
IVT Microbiology Week
2
IVT Microbiology Week
IVT Microbiology Week
• The
The speaker wish to thank IVT program manager speaker wish to thank IVT program manager
Curry Wilson, conference chair Karen Ginsburg, and event coordinator Kelly Carr for organizing this outstanding conference.
• Congratulations.
August 4, 2014
IVT Microbiology Week
3
Presentation Outline
• The intention of the USP Microbiology Committee of Experts
• Implementation of the USP Chapter
Implementation of the USP Chapter
• Expected impact of the new USP chapter <1115>
• Extent of microbial contamination of non‐sterile drug products
• Content of the USP Chapter <1115>
• Risk hierarchy by dosage form
Risk hierarchy by dosage form
• Factors increasing microbial contamination risk
• Drug substances
• Pharmaceutical excipients
• Drug Products
• Role of Manufacturing
Role of Manufacturing
August 4, 2014
IVT Microbiology Week
4
What is the USP?
What is the USP?
• The U.S. Pharmacopeial
p
Convention Inc. is an independent standards organization, founded in 1820, empowered by the U.S. Federal Food, Drug, and Cosmetic (FD&C) Act as the official drug
and Cosmetic (FD&C) Act as the official drug standard‐setting organization in the U.S. for drug p
products. • The Pharmacopeial Convention publishes and maintains the United States Pharmacopoeia (USP), N ti
National Formulary (NF), and USP Reference lF
l
(NF)
d USP R f
Standards and sets the quality standards for both drug products and pharmaceutical ingredients. gp
p
g
August 4, 2014
IVT Microbiology Week
5
U.S. Pharmacopeia
U.S. Pharmacopeia
• Hard Copy
Hard Copy
August 4, 2014
• Electronic
Electronic Copy
Copy
• May be download from the USP website: www.usp.org/usp‐
nf/offical‐text
IVT Microbiology Week
6
USP Intention
• The new USP Informational Chapter <1115> Bioburden Control of Non‐sterile Drug Substances and Products was published in the 2nd Supplement to USP37‐NF32 July 2014. What was the intent of the USP in publishing this chapter?
USP in publishing this chapter? • In the absence of regulatory guidance, the USP has provided a pragmatic scientific approach to the
provided a pragmatic scientific approach to the management of the microbial bioburden in non‐
sterile drug products in keeping with patient risk and gp
p g
p
contamination control objectives based on risk management principles. August 4, 2014
IVT Microbiology Week
7
USP Intention
USP Intention
• The
The chapter contains information on microbial chapter contains information on microbial
control considerations in product development, routine manufacturing, equipment design and use, microbial assessment of the non‐sterile manufacturing environment, active measures for microbial control, and the overall management of a i bi l
t l
d th
ll
t f
microbiological control program.
• Note: It is an informational chapter and not an Note: It is an informational chapter and not an
enforceable compliance document. August 4, 2014
IVT Microbiology Week
8
Presentation Outline
Presentation Outline
• The intention of the USP Microbiology Committee of Experts
• Implementation of the USP chapter
• Expected impact of the new USP chapter Expected impact of the new USP chapter <1115>
1115
• Extent of microbial contamination of non‐sterile drug products
• Content of the USP Chapter <1115>
Content of the USP Chapter <1115>
• Risk hierarchy by dosage form
• Factors increasing microbial contamination risk
• Drug substances
• Pharmaceutical excipients
• Role of Manufacturing
Role of Manufacturing
August 4, 2014
IVT Microbiology Week
9
Industry Implementation
Industry Implementation
• How
How should drug substance and drug product should drug substance and drug product
manufacturers react to the publication of this chapter? • I would hope that they should adopt a more risk‐
based approach to bioburden control in non‐sterile drug development and manufacturing based on an understanding of what determines the presence of microorganisms in their manufacturing facilities and
microorganisms in their manufacturing facilities and their persistence or proliferation in their drug products. products.
August 4, 2014
IVT Microbiology Week
10
Expert Opinion
Expert Opinion
• David
David Hussong, FDA CDER Microbiology Director, Hussong, FDA CDER Microbiology Director,
stated: “For the microbiologist, this (quality initiatives) emphasizes the importance of process knowledge to replace reliance on testing samples of finished product. Avoiding microbiological adulteration yields a more reliable indicator of d lt ti
i ld
li bl i di t
f
quality, which agrees with the assertion that quality cannot be tested into the product ”
cannot be tested into the product.
August 4, 2014
IVT Microbiology Week
11
Industry Implementation
Industry Implementation
• Manufacturers
Manufacturers should appreciate that whether should appreciate that whether
microorganisms found in a non‐sterile product will be objectionable in that product depends their number and species, the product attributes, dosing regimen, route of administration, and targeted patient population. ti t
l ti
• Any environmental monitoring program would be risk based in terms of sample selection and
risk‐based in terms of sample selection and frequency and would be used to confirm microbial control and would not be linked to product release.
control and would not be linked to product release.
August 4, 2014
IVT Microbiology Week
12
Presentation Overview
•
•
•
•
•
•
•
•
•
•
•
The intention of the USP Microbiology Committee of Experts
Implementation of the USP Chapter
Expected impact of the new USP chapter <1115>
Extent of microbial contamination of non‐sterile drug products
Content of the USP Chapter <1115>
Risk hierarchy by dosage form
Risk hierarchy by dosage form
Factors increasing microbial contamination risk
Drug substances
Pharmaceutical excipients
Drug Products
Role of Manufacturing
August 4, 2014
IVT Microbiology Week
13
Industry Impact
Industry Impact
• What is the expected impact of the USP chapter?
at s t e e pected pact o t e US c apte
• The expectation is there would be improved and cost‐
effective bioburden controls for non‐sterile drug products to a level consistent with patient safety. • This may reduce product recalls for microbial contamination.
t i ti
• Manufacturers will be able to benchmark their bioburden control programs against the
bioburden control programs against the recommendations within the chapter and adjust their programs accordingly.
August 4, 2014
IVT Microbiology Week
14
Presentation Outline
Presentation Outline
• The intention of the USP Microbiology Committee of Experts
• Expected impact of the new USP chapter <1115>
• Extent of microbial contamination of non‐sterile drug Extent of microbial contamination of non sterile drug
products
• Content of the USP Chapter <1115>
• Risk hierarchy by dosage form
• Factors increasing microbial contamination risk
• Drug substances
Drug substances
• Pharmaceutical excipients
• Role of Manufacturingg
August 4, 2014
IVT Microbiology Week
15
Microbial Contamination
Microbial Contamination
• The
The contamination of marketed products with contamination of marketed products with
objectionable microorganisms continues to be an infrequent but chronic problem for our industry.
• There are the order of 20 U.S. recalls on non‐sterile products annually for microbial contamination.
August 4, 2014
IVT Microbiology Week
16
What are Objectionable Microorganisms?
What are Objectionable Microorganisms?




They are defined by specific dosage forms.
They include specified microorganisms, frank pathogens and opportunistic pathogens that are known from the clinical literature to cause
known from the clinical literature to cause infection in the recipient via the route of administration or microorganisms that grow in the product overcoming the preservative system
p
g
p
y
Also, they may include organisms associated with major recalls for microbial contamination
If these microorganisms are present in the drug
If these microorganisms are present in the drug product below the microbial limit, the batch would be rejected.
August 4, 2014
IVT Microbiology Week
17
U.S. Congressional Hearings
U.S. Congressional Hearings
August 4, 2014
IVT Microbiology Week
18
U.S. Recalls
• A recent U.S. survey reported 144 recalls composed of non‐sterile
of non
sterile branded pharmaceutical drug branded pharmaceutical drug
products (5%), over‐the‐counter drug products (
(42%), cosmetics (31%), medical devices (14%) and )
(
)
(
)
dietary supplements (8% of the total recalls) for microbiologically‐related issues for the 7‐year period from 2004 through 2011 f
h
h
• The survey highlighted that the majority of these recalls (72%) were associated with objectionable ll (72%)
i t d ith bj ti
bl
microorganisms and not for exceeding the microbial enumeration limits (Sutton and Jimenez 2012)
enumeration limits (Sutton and Jimenez, 2012). August 4, 2014
IVT Microbiology Week
19
Microorganisms Implicated
Microorganisms Implicated
• The
The most frequently cited microorganisms in the most frequently cited microorganisms in the
recalls were the Burkholderia cepacia complex (34 occurrences), unspecified fungal contamination (19 occurrences), Bacillus cereus (9 occurrences), Pseudomonas aeruginosa (6 occurrences), Eli b thki i
Elizabethkingia meningoseptica
i
ti (5 occurrences), (5
)
Enterobacter gergovia (5 occurrences), Pseudomonas putida (3 occurrences), Pseudomonas Pseudomonas putida
(3 occurrences) Pseudomonas
spp. (2 occurrences) and Salmonella spp. (2 occurrences). )
August 4, 2014
IVT Microbiology Week
20
Burkholderia cepacia Complex
Burkholderia cepacia Complex
• The
The prominence of the Gram
prominence of the Gram‐negative,
negative, oxidase
oxidase‐
positive bacterium B. cepacia in non‐sterile product recalls is the result of it prevalence in water, metabolic versatility, and its resistance to many disinfectants and antimicrobial preservative systems.
t
• B. cepacia is a common opportunistic pathogen and infects cystic fibrosis sufferers
infects cystic fibrosis sufferers.
August 4, 2014
IVT Microbiology Week
21
Unidentified Fungi
Unidentified Fungi
• The
The second most prevalent recall category was second most prevalent recall category was
unidentified fungi. This reinforces that pharmaceutical microbiologists do a poor job identifying mold.
• For further information see Cundell, A. M. 2013 Mold Contamination in Pharmaceutical Drug products and Medical Devices European Pharmaceutical Review 18 (6): 67 75
Pharmaceutical Review 18 (6): 67‐75
August 4, 2014
IVT Microbiology Week
22
Presentation Outline
Presentation Outline
• The intention of the USP Microbiology Committee of Experts
• Expected impact of the new USP chapter <1115>
• Extent of microbial contamination of non‐sterile drug Extent of microbial contamination of non sterile drug
products
• Content of the USP Chapter <1115>
• Risk hierarchy by dosage form
• Factors increasing microbial contamination risk
• Drug substances
Drug substances
• Pharmaceutical excipients
• Role of Manufacturingg
August 4, 2014
IVT Microbiology Week
23
Contents of the USP Chapter
p
• Introduction
• Risk Hierarchyy
• USP <61>, <62> and <1111>
• US Regulatory Guidance Documents
• Microbial Control Consideration During Product Development
• Microbial Control Consideration During i bi l C
l C id
i
i
Manufacturing
• Microbial Control of Drug Substance Manufacturing
Microbial Control of Drug Substance Manufacturing
– Equipment Design and use
– Personnel
– The Manufacturing Environment
Th M
f
i E i
August 4, 2014
IVT Microbiology Week
24
Content of the USP Chapter
Content of the USP Chapter
• Microbial
Microbial Assessment of Non
Assessment of Non‐sterile
sterile Product Product
Manufacturing Environment
– Microbial Sampling
– Microbial Identification
– Active Measures for Microbial Control
• Overall
Overall Management of a Microbiological Control Management of a Microbiological Control
Program
• References
August 4, 2014
IVT Microbiology Week
25
Presentation Outline
Presentation Outline
• The intention of the USP Microbiology Committee of Experts
• Expected impact of the new USP chapter <1115>
• Extent of microbial contamination of non‐sterile drug Extent of microbial contamination of non sterile drug
products
• Content of the USP Chapter <1115>
• Risk hierarchy by non‐sterile dosage form
• Factors increasing microbial contamination risk
• Drug substances
Drug substances
• Pharmaceutical excipients
• Manufacturingg
August 4, 2014
IVT Microbiology Week
26
Risk Hierarchy
Risk Hierarchy
Hierarchy of risk due to microbial contamination by route of administration (High to low):
route of administration (High to low):
•
•
•
•
•
•
•
•
•
Metered‐dose and dry powder inhalants
Nasal sprays
p y
Otics
Vaginal suppositories
Topicals
Rectal suppositories
Oral liquids (aqueous)
Liquid‐filled capsules
Compressed tablets and powder filled capsule
Compressed tablets and powder‐filled capsule
August 4, 2014
IVT Microbiology Week
27
Presentation Outline
Presentation Outline
• The intention of the USP Microbiology Committee of Experts
• Expected impact of the new USP chapter <1115>
• Extent of microbial contamination of non‐sterile drug Extent of microbial contamination of non sterile drug
products
• Content of the USP Chapter <1115>
• Risk hierarchy by dosage form
• Other factors increasing microbial contamination risk
• Drug substances
Drug substances
• Pharmaceutical excipients
• Manufacturingg
August 4, 2014
IVT Microbiology Week
28
Increased Microbial Risk
Increased Microbial Risk
• The development of novel drug delivery systems e g dry powder inhalants nasal sprays
e.g., dry powder inhalants, nasal sprays, transdermal patches, and drug‐coated transplanted medical devices that may increase patient risk to microbial contamination due to ti t i k t
i bi l
t i ti d t
their invasiveness within the human body.
• The sourcing of drug substances from The sourcing of drug substances from
manufacturing facilities in third‐ world countries with increased risk of potential product contamination due to poor GMPs
contamination due to poor GMPs
• Globalization with drugs manufactured outside the US and transported around the world.
the US and transported around the world.
August 4, 2014
IVT Microbiology Week
29
Increased Microbial Risk
Increased Microbial Risk
• The
The growth of off
growth of off‐label
label dosage regimes and dosage regimes and
patient populations as physicians seek wider clinical applications and change administration pp
g
practices.
• The increased aggressiveness and invasiveness The increased aggressiveness and invasiveness
of medical treatments.
• Increases in patients who due to their age or Increases in patients who due to their age or
medical condition are seriously immunologically compromised and are aggressively treated.
p
gg
y
August 4, 2014
IVT Microbiology Week
30
Presentation Outline
Presentation Outline
• The intention of the USP Microbiology Committee of Experts
• Expected impact of the new USP chapter <1115>
• Extent of microbial contamination of non‐sterile drug Extent of microbial contamination of non sterile drug
products
• Content of the USP Chapter <1115>
• Risk hierarchy by dosage form
• Factors increasing microbial contamination risk
• Drug substances
Drug substances
• Pharmaceutical excipients
• Manufacturingg
August 4, 2014
IVT Microbiology Week
31
Drug Substances
Drug Substances
• The bioburden of DS manufactured by y
chemical synthesis will largely depend on the final synthetic, isolation and purification steps the drying process micronization for
steps, the drying process, micronization for particle size reduction, and to a lesser extent the drug substance packaging. g
p
g g
• In general, the chemical transformations and isolation of intermediates typically involve reactions using reagents, solvents, and i
i
l
d
elevated temperatures that are incompatible with the survival of microorganisms
with the survival of microorganisms. August 4, 2014
IVT Microbiology Week
32
Chemical Synthesis
Chemical Synthesis
August 4, 2014
IVT Microbiology Week
33
Drug Substances
Drug Substances
• The
The bioburden of the starting materials, bioburden of the starting materials
reagents, and intermediates will have little or no impact on the bioburden of the drug
no impact on the bioburden of the drug substances and may be discounted. • The bioburden of a plant‐
The bioburden of a plant or animal‐derived or animal derived
drug substance will depend on the degree of processes of the material
processes of the material.
August 4, 2014
IVT Microbiology Week
34
Drug Substances
Drug Substances
• The impact of the final purification and isolation e pact o t e a pu cat o a d so at o
steps on the DS bioburden depends on the solvent used in the mother liquor, temperature of the isolation process, the inclusion of a f h
l
h
l
f
bioburden‐controlling filtration step, the material recovery method and drying process
material recovery method, and drying process. • Typically 90% of the isolations employ organic solvent or a mixture of organic solvents and
solvent or a mixture of organic solvents and water and not water, which reduces the likelihood of microbial contamination. August 4, 2014
IVT Microbiology Week
35
Drug Substances
Drug Substances
• The most common organic solvents used in g
industrial organic syntheses include toluene, tetrahydrofuran, dichloromethane, ethyl acetate 2 propanol methanol denatured
acetate, 2‐propanol, methanol, denatured alcohol, acetic acid, n‐heptane, and acetronitrile. All are inimical to the survival of microorganisms
• If water is the primary solvent, purified water, USP is used for DS used in non‐sterile i
df
di
il
drug products and low‐endotoxin purified water in sterile drug products
water in sterile drug products.
August 4, 2014
IVT Microbiology Week
36
Product Development
Points to be considered when assessing the potential microbial risk associated with non‐sterile d
drug products:
d t
•
•
•
•
•
•
•
•
•
•
Synthesis, isolation and final purification of the drug substance
Microbiological attributes of the drug substance
Microbiological attributes of the drug substance
Formulation and physicochemical attributes of the drug product
Water activity of the drug product
Manufacturing process
Packaging and delivery system
Storage conditions of the drug substance and product
Storage conditions of the drug substance and product
Route of administration
Expected treatment procedure and dosage regimen
Age and health condition of the intended recipients of the drug
August 4, 2014
IVT Microbiology Week
37
U.S. Regulatory Documents
U.S. Regulatory Documents
• FDA
FDA Good Manufacturing Practices found in 21 CFR Good Manufacturing Practices found in 21 CFR
Part 211
• 211.42 Design and Construction
• 211.46 Ventilation, Air Filtration. Air heating and Cooling
• 211.56 Sanitation
• 211.113 Control of Microbiological Contamination
August 4, 2014
IVT Microbiology Week
38
Manufacturing Risk Factors
Manufacturing Risk Factors
Microbial risk factors in descending order:
Microbial risk factors in descending order:
•
•
•
•
•
Ingredient water
Pharmaceutical ingredients
g
Processing equipment
Manufacturing personnel
Manufacturing environment
August 4, 2014
IVT Microbiology Week
39
Pharmaceutical Water Systems
Pharmaceutical Water Systems
August 4, 2014
IVT Microbiology Week
40
Classification of Pharmaceutical Excipients
•
•
•
•
•
Binders
Disintegrants
Fillers (diluents)
Lubricants
Glidants (flow enhancers)
• Compression aids
• Colors
l
• Sweeteners
August 4, 2014
•
•
•
•
Caking agents
Caking
agents
Buffers
Preservatives
Suspending/dispersing agents
• Film formers/coatings
• Flavors
• Printing inks
IVT Microbiology Week
41
Common Excipients used in Solid Dosage Forms
Excipient
Classification
Common Excipients
Diluent or Filler
Lactose, Sucrose, Kaolin, Dibasic Calcium Phosphate,
Calcium Sulfate, and Calcium Carbonate
Binders
Water, Alcohol
Water
Alcohol, Starch Paste
Paste, Gelatin Solutions
Solutions,
Tragacanth, Sodium Alginate, Carboxymethyl
Cellulose, Polyethylene Glycol and Povidone
Lubricants
Magnesium Stearate,
Stearate Calcium Stearate,
Stearate Talc
Talc, Stearic
Acid, Starch, Mineral Oil, Sodium Chloride, Sodium
Benzoate, and Carbowax 4000 or 6000
Disintegrating
Agents
Corn Starch
Starch, Methylcellulose
Methylcellulose, Sodium Carboxymethyl
Cellulose, Alginic Acid, Microcrystalline Cellulose and
Gums
g
Sweetening
Agents
Mannitol,, Lactose,, Sorbitol,, Fructose,, Saccharine,, and
Aspartame
August 4, 2014
IVT Microbiology Week
42
Risk Analysis of Pharmaceutical Excipients
Classification
Examples of Excipients
y
Synthetic Material
Povidone (polyvinyl pyrrolidone) and (p y y py
)
Crospovidone (A homopolymer of cross‐
linked N‐vinyl‐2 pyrrolidone)
Semi‐synthetic y
Captisol (Chemically‐modified cylodextrin) p
(
y
y
)
material
and Hydroxypropyl Methylcellulose
Microbial Risk
Little or none
Low to moderate
Plant‐derived Corn Starch, Microcrystalline Cellulose, and Moderate
Material
Sucrose
Animal‐
derived Material
Lactose (Extractive), Magnesium Stearate (Processed chemically from tallow), and Gelatin (Purified from bone or hide)
Gelatin (Purified from bone or hide)
Moderate to high
Mineral‐
derived Material
Talc (Extractive) and Dibasic Calcium Phosphate (Processed chemically from a mineral calcium carbonate and phosphoric
mineral calcium carbonate and phosphoric acid)
Low to moderate
August 4, 2014
IVT Microbiology Week
43
Talc Mining
Talc Mining
August 4, 2014
IVT Microbiology Week
44
Lactose Production
Lactose Production
• Whey protein concentrates are powder made by drying yp
p
y y g
the retentate from the Ultra Filtration of whey. The concentration of whey proteins is primarily achieved by UF and Diafiltration
UF and Diafiltration.
• The permeate of UF membrane is high in lactose content, so that is used for manufacturing lactose powder. Permeate recovered is concentrated to d
di
d
minimum 62% TS level in an evaporator and then cooled under controlled conditions for Lactose crystallization. Crystals are washed, decanted and spray dried to produce pharma grade lactose.
August 4, 2014
IVT Microbiology Week
45
Lactose Manufacturing
Lactose Manufacturing
• Lactose spray dryer
Lactose spray dryer
August 4, 2014
IVT Microbiology Week
46
Risk Assessment
Risk Assessment



In Failure Mode and Effects Analysis (FMEA) terms y (
)
risk was defined in terms of occurrence (O), severity (S) and detection (D). The risk is expressed as O x S X D Using this tool risk is minimized if occurrences
D. Using this tool, risk is minimized if occurrences decrease, severity of the effect of failure is decreased, and the efficiency of detection of a failure increases. Note: The less readily that microbial contamination can be detected the higher the value of D and the overall risk
overall risk.
For a discussion of risk analysis see ICH Q9 Quality Risk Management
August 4, 2014
IVT Microbiology Week
47
Simple Risk Analysis
Simple Risk Analysis
An approach is to assign a score from 1 to 3 to pp
g
the following:
• Severity (S) as a consequence of failure
• Occurrence (O) as the likelihood of failure occurring based on past experience
• Detection (D) as the likelihood that failure detection will take place with the proposed monitoring system
• The risk is determined by the product of S x O x D
D
August 4, 2014
IVT Microbiology Week
48
Risk Analysis – Occurrences (O), Susceptibility (S) and Detectability (D)
bl ( ) d
bl ( )
Excipient
p
Manufacturing
Process
O
S
D
OxSxD
Synthetic Material
1
2
1
2
Semi-synthetic
material
1
2
2
4
Plant-derived
Material
2
3
2
12
Animal-derived
Animal
derived
Material
3
3
2
18
Mineral-derived
Material
2
2
2
8
August 4, 2014
IVT Microbiology Week
49
ICH Q6A
ICH Q6A
• For drug product release testing, ICH Q6A Test gp
g,
Q
Procedures and Acceptance Criteria for New Drug Substances and Drug Products provides decision trees that guide manufacturers on necessary test
trees that guide manufacturers on necessary test strategies based on the nature of the product.
The establishment of microbiological attributes are
• The establishment of microbiological attributes are described in Decision Tree 6 (Drug Substances) and Decision Tree 8 (Drug Products).
• Low water activity is a highlighted attribute for reduced testing strategies.
August 4, 2014
IVT Microbiology Week
50
Manufacturing Environment
Common design elements to control microbial contamination:
• Non‐porous walls, ceilings and floors that are readily cleanable
• Floor drains that can be closed during processing or fitted with a air break if opened during area and equipment cleaning
• Access should be limited to essential personnel
• Material, equipment and personnel flows should avoid M t i l
i
t d
l fl
h ld
id
contamination
• Ventilation and air filtration should be adequate to maintain q
the specified cleanliness, space pressurization, temperature and humidity August 4, 2014
IVT Microbiology Week
51
Manufacturing Equipment
Manufacturing Equipment
For bioburden control equipment should have the For
bioburden control equipment should have the
following attributes:
• Sanitary design
y
g
• Readily cleaned preferably using a CIP system
Self‐draining
draining to eliminate stagnate water
to eliminate stagnate water
• Self
• Preventative maintenance program to periodically replace valves, seals, filters and hosing
p
,
,
g
• Inclusion of microbial monitoring in cleaning validation protocols
p
August 4, 2014
IVT Microbiology Week
52
Dosage Forms
Dosage Forms


Over 80% of the current drug products by the number of prescription are marketed as oral solid
number of prescription are marketed as oral solid dosage forms, i.e. powder‐ and liquid‐ filled capsules and compressed tablets, which have a very low risk of microbial contamination because of their manufacturing processes, low water activity and route of administration
route of administration. Many other non‐sterile drug products, e.g., oral liquids, topicals, nasal sprays, etc, may be q
, p
,
p y, ,
y
susceptible to microbial growth and have more critical routes of administration than an oral solid. August 4, 2014
IVT Microbiology Week
53
Risk Assessment
Risk Assessment
What other tools are available for this risk assessment?  In the 1960's, the Pillsbury Company, the U.S. Army, and National Aeronautics and Space Administration (NASA) i t d d
(NASA) introduced a system for assuring pathogen‐
t
f
i
th
free foods for the space program.  This system, called Hazard Analysis and Critical This system, called Hazard Analysis and Critical
Control Points (HACCP), is a focus on critical food safety areas as part of total quality programs and may be a tool applicable to the pharmaceutical industry
be a tool applicable to the pharmaceutical industry. August 4, 2014
IVT Microbiology Week
54
HACCP
• HACCP
HACCP involves a critical examination of the involves a critical examination of the
entire food manufacturing process to determine every step where there is a
determine every step where there is a possibility of physical, chemical, or microbiological contamination of the food
microbiological contamination of the food, which would render it unsafe or unacceptable for human consumption. These
unacceptable for human consumption. These identified points are the critical control points (CCP).
points (CCP). August 4, 2014
IVT Microbiology Week
55
HACCP
There are seven principles to HACCP:
There
are seven principles to HACCP:
1. Analyze hazards, 2 determine CCPs
2. determine CCPs, 3. establish critical limits, 4 establish monitoring procedures
4. establish monitoring procedures,
5. establish deviation procedures, 6 establish verification procedures and
6. establish verification procedures, and 7. establish record keeping procedures
August 4, 2014
IVT Microbiology Week
56
Tablet Manufacturing
Tablet Manufacturing


In general, the most critical processing steps with g
,
p
g p
respect to potential microbial contamination are the procurement of pharmaceutical ingredients, wet granulation and milling and tablet coating
wet granulation and milling and tablet coating (Bolded red in list of manufacturing steps). For example, the holding time of aqueous film coating p
g
q
g
solutions may be a critical control point.
In contrast, fluid bed drying and compression are potentially bioburden‐reduction steps (Bolded t ti ll bi b d
d ti
t
(B ld d
green) August 4, 2014
IVT Microbiology Week
57
Tablet Manufacturing
Tablet Manufacturing
For example, the processing steps for the manufacture of a film‐coated
of a film
coated compressed tablet are:
compressed tablet are:
 Procurement of pharmaceutical ingredients
 Warehousing pharmaceutical ingredients
 Batching of the pharmaceutical ingredients
 Blending
 Wet granulation and milling
l i
d illi
 Drying
 Tablet compression
Tablet compression
 Tablet coating
 Packaging
g g
 Distribution
August 4, 2014
IVT Microbiology Week
58
Tablet Manufacturing
Tablet Manufacturing
• Unit
Unit processes involved in making tablets include processes involved in making tablets include
particle size reduction and sizing (milling), blending, granulation, drying, compaction (compression), (frequently) coating and packaging.
August 4, 2014
IVT Microbiology Week
59
Tablet Manufacturing
Tablet Manufacturing
August 4, 2014
IVT Microbiology Week
60
Risk Analysis for Tablet Manufacturing
Risk Analysis for Tablet Manufacturing
Manufacturing
Step
Contamination Preventative
Potential
Measures/Critical
Control Points
Remarks
Wet granulation
and milling
Moderate
Emphasis on water
system validation and
equipment cleaning to
prevent microbial
contamination. Water
activity measurement
may be used to evaluate
the ability of the
granulation to support
microbial growth
August 4, 2014
Equipment design.
Cleaning
validation.
Monitor purified
water used in
granulation
solutions for
microbial counts
(CCP). Holding
Time (CCP).
IVT Microbiology Week
61
Risk Analysis for Tablet Manufacturing
Risk Analysis for Tablet Manufacturing
Manufacturing
Step
Contamination
Potential
Preventative
Measures/Critical
Control Points
Remarks
Tablet Coating
Moderate to
High
Equipment
cleaning and
solution holding
time (CCP)
Incoming
microbial testing
of ingredients
(CCP)
Monitor purified
water used in
coating solutions
for microbial
counts (CCP)
Water-based
coating
solution will
support
microbial growth.
Holding times
need to be
justified.
August 4, 2014
IVT Microbiology Week
62
Risk Analysis
Risk Analysis
• After Anastasia Lois, 2013
After Anastasia Lois, 2013
August 4, 2014
IVT Microbiology Week
63
Conclusions
The management of a successful microbiological g
g
control program includes the following: • Identification of suitable suppliers of pharmaceutical ingredients and excipients that have h
l
d
d
h h
good microbiological quality
• Conducting a microbial risk assessment of the drug Conducting a microbial risk assessment of the drug
formulation, manufacturing process and packaging system and mitigating those risks
• The establishment of an appropriate monitoring and control system.
August 4, 2014
IVT Microbiology Week
64
Contact Information
Contact Information
• Tony Cundell, Consulting Microbiologist
Tony Cundell, Consulting Microbiologist
• Email address: [email protected]
• Phone number: 01 914 725
Phone number: 01 914 725‐3947
3947
August 4, 2014
IVT Microbiology Week
65