By Herbert N. Prince, Ph.D. and Daniel L. Prince, Ph.D. Gibraltar Labs, Inc.

I

 N FEBRUARY OF 1965 PROFESSOR L.W. Kallings appeared before the Swedish National Board of Health in Stockholm and advised, "We have typhoid fever. We have deaths." He was asked to write a report, in which he concluded, "it is nei­ther from food nor water, it's from a medicine."

We now know that Prof. Kallings had detected strains of Salmonella in a standard oral drug, a dry thyroid powder from domestic animals that was not much changed from the 1940 edition of USP VI The drug was Thyroideum, U.S.P. In the same year, Prof. Kallings wrote a second report to the Swedish National Board of Health entitled, "Microbiological Contam­ination of Medical Preparations". In 1966 he expanded his investigation of contamination in the Pharma industry and reported that blindness and eye infections were due to ophthalmics contaminated with Pseudomonas aeruginosa. In 1967 the Swedish National Board published the first manu­facturing guide on Contamination Control, "Production, Hygiene and Bacteriological Control in the Manufacture of Pharmaceuticals".

In these same years the FDA published surveys of Pseudomonas, Serratia and Klebsiella infections, all from aqueous eye makeups, creams, topical drugs, baby lotions, liquid soap, and skin antiseptics. Children died in a Texas hospital follow­ing application of a baby lotion to the umbilicus, and iodophor solutions in a Massachusetts hospital were found to be con­taminated with Pseudomonas cepacia in instances too numerous to count. In a rapid turnaround, USP 18 (1970) switched its sole

attention from sterility tests and antibiotic assays to non-sterile drugs and "Contamination Control," the subject of this article some 35 years later.

The historic fountainhead for the field of contamination con­trol was the USP 18 Chapter, "Microbial Limits Test". The fields of "Contamination Control" and "Water Validation" were thus born. Shortly after publication of USP 18, a series of deaths occurred nationwide from a large volume parenteral, intra­venous infections and endotoxin shock from a product that passed the USP sterility test. In court the FDA lost its case against the manufacturer because the manufacturer had per­formed the sterility test as promulgated in USP 18 (liquid con­tents) and did not test the screw cap because it "didn't have to." By using a swab and not a membrane filtration apparatus, the FDA found that when the bottle was turned upside down, the gram negative rods were transferred from liner to drug and no one, not even the nurses, noticed that they were infusing a cloudy suspension into the vein. It was not reported because "they didn't have to." Thus the field of "validation" was born. "Process Control" trumped "Final Product Testing" and the modern era of Contamination Control was on the march for all pharmaceutical dosage forms, sterile, non-sterile, prescription or over-the-counter. This is our subject.

Dr. Herbert N. Prince is founder of Gibraltar Laboratories. Dr. Daniel L. Prince is president of Gibraltar Laboratories. They can be contacted at danielprince@gibraltarlabsinc.com or hprince@gibraltarlabsinc.com.

2 CONTRACT PHARMA • June 2005

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MICROBIOLOGY

This article, which is based on historic as well as current knowledge, is intended to act as a basic primer for microbiolo­gists and manufacturing personnel on the relationship be­tween the microbial world and the quality, safety and efficacy of pharmaceutical articles. It contains some important informa­tion from USP publications. There is a lurking microbial cloud which can be transported silently from the outermost Class 100,000 portions to the innermost critical areas, putting prod­uct, consumer and company at risk. The physical, behavioral and chemical interventions that prevent this "invasion" will be discussed.

The subject of Contamination Control describes the meth­ods for detecting, removing and destroying the microorgan­isms that might become resident in critical and non-critical areas of manufacture. We address how we can measure a pop­ulation of microorganisms and how the application of trend analysis and adherence to standards can enhance the goal of quality.

We will deal heavily with experimental data, moving from theory to practice. In so doing we review some prior experi­mental data published from this laboratory and elsewhere, with references and attribution. The paper also contains certain unpublished data on the distribution, identification and control of bacteria, fungi and viruses, with special reference to the use of chemical germicides, a subject now receiving high priority from the expert committee of the current USP. The sections pro­vided on growth, desiccation resistance and sensitivity or resistance to disinfectants, and choice of germicides, help to establish the subtitle of this article: "The Life and Death of Bacteria and Other Germs".

Organisms found in the Pharmaceutical Manufacturing Environment

A review of isolations obtained from Class 100,000 and 10,000 areas was conducted in a search for bacteria, yeasts and molds. That data are summarized in Table 1.

It is noted that 42% of the isolates consisted of Gram-posi­tive organisms, a finding consistent with our D-10 desiccation resistance data table 3. The low number of Gram-negative rods isolates (10%) is also consistent with D10 desiccation resistance data. An analysis of speciation revealed that non-pathogens were the predominant flora.

Table 2 Surfaces to be decontaminated by disinfectants in non-sterile and sterile product manufacturing areas

Material

Application

Stainless steel

Filling equipment, tanks, etc.

Glass

Windows, vessels

Plastic,Vinyl

Curtains

Plastic, polycarbonate

Insulation coating

Plexiglass

Shields

Epoxy coated gypsum,

Fiberglass plastic

Walls and ceilings

Tyvek

Equipment wraps

Terrazzo tiles

Floors

Various materials

Fixtures, shelving, cabinets, teflon

surfaces, bench surfaces

Metals

Door knobs, equipment

Table I An analysis of 315 environmental cultures from manufacturing sites, air and surfaces (Class 10,000; 100,000)

Type of

organisms

% of time

recovered

 

All bacteria (ubiquitous)

52%

 

Diphtheroids (Skin)

I %

 

Gram-negative rods (soil, dust, skin, etc)

10%

Group I

Gram-positive bacillus (spore formers) (vegetation soil)

25%

 

Gram positive cocci (many species of staphylococci and

micrococci) (soil, human, skin, vegetation, etc.)

16%

Group 2

Yeast (vegetation, skin, soil)

I %

Group 3

Filamentous fungi (ubiquitous) (mostly class 100,000)

48%

The detection of organisms on environmental and equip­ment surfaces is Part I of a contamination control program. Part II is to determine how they can be eliminated and Part III speaks to the issue of propagation dissemination (in other words how did they get there?). When EPA-registered disinfec­tants are used it must be pointed out that they have been test­ed primarily against human or veterinary pathogens and not environmental isolates. They are approved only for non-porous hard surfaces. EPA-registered commercial disinfectants are not certified for any surface of a physical nature that departs even slightly from polished stainless steel. EPA-registered disinfectants are approved to kill at least 10,000 organisms in 10 minutes or less. Given the clean state of most phar­maceuticals surfaces, a lesser applica­tion is probably effective.

The Survival of Microorganisms on Surfaces in the Absence of Disinfectants

Table 3 presents current and previously reported data (Prince 1984) on the life and death of a variety of bacteria, yeasts, molds and viruses on the type of surfaces in Table 2.

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MICROSIOLOGY

Table 3 Approximate Scale of Resistance on Hard Surfaces

The data in Table 3 (showing a high degree of desiccation resistance for the Gram Positive bacteria) agree with the data in Table 1 in which it was shown that the majority of bacteria isolated from environmental surfaces are of the Gram Positive variety. Once deposited on any inanimate surface in the Pharma manufacturing area, growth is nearly impossible, with the exception of excessive relative humidity and incom­plete removal of organic matter, which can trigger extensions in viability.

DISINFECTANTS

A USP informational chapter on disinfectants has been circu­lated for comments, indicating a tremendous interest in the use and effectiveness of chemical germicides in the drug industry. A general discussion seems warranted. Disinfectants generally used in pharmaceutical manufacturing fall into three cate­gories:

a) Sporicides (chemosterilizers): consisting usually of oxidiz­ing agents (e.g. bleach, peroxides, peracetic acid). These are rapidly active and kill most microorganisms they encounter. However, some spores are resistant. These products can be corrosive and irritating.

b) Alcohols (disinfectants): as either ethanol or isopropanol. Some are made sterile by membrane filtration or irradiation. They are fast acting but must be left in contact long enough to avoid evaporation. In the laboratory they can kill vegeta­tive bacteria in seconds. They have no immediate effect on spores. Their action against filamentous molds is not as fast as against bacteria.

c) General disinfectants (quaternary ammonium compounds "quats" and phenolics): either type of product can consist of a single active compound or mixtures of different structures within the molecular species. The quaternary compounds

Organism

-DIo

Susceptibility

 

Value*

Groupa

P. aeruginosa, E. coli, S. epidermidis

I - 2 hours

A

P. acnes, S. choleraesuis, Enterobacter, S. pullorum,

4 - 5 hours

B

Influenza A virus,

 

 

A. niger, Herpes simplex I,Vaccinia virus, Penicillium,

7 - 9 hours

C

Paecilomyces

 

 

Poliovirus, coxsackie, HAV

13 hours

D

S. aureus, S. warneri, S. hermanii, C. albicans,

6 - 20 hours

E

S. hominis, S. simulans

 

 

M. luteus, M. lylae

48 hours

F

B. pumilus, 8. cereus, B. subtilis, 8 onthracis (spores)

-3 years

G

'Increasing resistance to ambient desiccation

xD = length of time for dried population time

to decrease ]-log (90%) calculated as D -

logNo-logN i

can kill more rapidly than the phenolics, and are more soluble. They also provide detergency. The advantage of phenolics is that they kill TB and hydrophilic viruses (e.g., polio). But since these organisms are rarely found as contami­nants in the pharmaceutical industry, the value of these traits is limited. As with antibiotics there are first, second and third generation quats and pheno­lics, with improvements centering around enhanced spectra, speed of action and resistance to hard water. In general, quats, halogens, alcohols and phenolics kill in seconds when in sus­pension, but kill slowly when exposed to organisms in the dry state. Many firms challenge commercial disinfec­tants with organism isolates from the manufacturing environment.

d) The rotation of disinfectants is unnecessary except in food establish­ments, as we have written in a previous publication, because selection of theo­retical mutants is unlikely. (Prince, 1984)

e) Any credible use of disinfectants (an intervention as critical as air filtration in contamination control) requires knowl­

Table 4 Approximate Disinfection Scale for all Organisms in Order of Increasing Resistance (Response to Commercial Disinfectants) (after Prince and Prince, Block 2001)

Microbial

Microorganisms

susceptibility

(dried on carriers)

group

 

A

Retroviruses (AIDS), ortho and paramyxo­

 

viruses, herpes viruses (enveloped

 

lipophiles), vaccinia, corona, other

 

enveloped viruses, gram-negative rods and

 

some filamentous fungi; some gram-positive

 

cocci, human hepatitis B and C viruses

B

Staphylococcus aureus, some diphasic and

 

filamentous fungi, yeasts and algae, some

 

gram-negative rods

C

Adenoviruses (capsomeric lipophiles)

D

Mycobacterium tuberculosis (BCG strain),

 

rotaviruses, reoviruses, some mold

 

ascospores

E

Picornaviruses (polio, rhino) Parvoviruses

 

(SS DNA), hepatitis A

F

Bacterial endospores (Bacillus, Clostridium);

 

viroids (Plant RNA)

G

Prions (TDE Agents or "Mad Cow")

4    CONTRACT PHARMA *June 2005

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edge of how sensitive or resistant the environmental biobur­den is. We have studied this problem and a scale of disin­fectant effectiveness was published earlier (part of this is summarized in table 4).

The data in Table 4 show the difference in susceptibility of the various microorganisms to standard EPA registered disin­fectants. Again as shown in Table 3 (desiccation resistance) S. aureus was among the more resistant bacteria. Our studies were further analyzed using stainless steel AOAC/EPA use dilution method in terms of what percent were killed by com­mercial disinfectants (Table 5).

Table 5 Effectiveness of Commercial Quaternary and Phenolic Disinfectants against Plant Isolates

Type

# species isolated

% Fail

AOAC/E PA Test

Bacteria (vegetative)

24

29%

Fungi

39

41%

Bacillus (spores)

9

100%

Current Status of USP Microbiology In Contamination Control

The current edition of USP 27 contains articles on contamina­tion control and a partial list is provided. All are available on the Internet.

l. Chapter 61. This chapter, entitled Microbial Limits Test is essentially unchanged since its inception 35 years ago. This landmark collection of methods is the ultimate arbiter of whether or not a non-sterile article is free of microbial adul­teration. It has been copied worldwide The current chapter is being divided into two portions, one to cover the total bacte­rial and mold count (quantitative chapter) and a new section (chapter 62) that speaks to the detection of certain objection­able or indicator organisms, Staphylococcus aureus, Escherichia coli, Salmonella species, Pseudomonas aeruginosa, Candida albi­cans and Clostridium species (qualitative chapter). A valuable new statistical concept is proposed that will loosen the guidelines on counting bacteria. Thus, when counts are spo­ken of as in the order of 10 per gram, this can be as large as 20 CFU/gram, likewise 100 per gram and 1000 per gram (and so on) can be construed 200 and 2000, respectively.

The results summarized in Table 5 with Bacteria and Fungi are not unexpected since commercial disinfectants are rarely tested against wild-type environmental organisms as part of EPA pre-market approval. The results with spores were pre­dictable with these types of agents. When chemosterilizers were used (oxidizers) such as 10% (0.525% Sodium hypochlo­rite) bleach, all bacterial spores were killed.

Sources and Control of Microbial Contaminants The reduction transit from class 100,000 to an ultimate aseptic area requires intervention in five areas as shown in Table 6:

Table 6 Sources and Control of Contaminants -

A General Guide

Source

Control

Air

HEPA filtration, UV

Environmental Surfaces

Cleaning, Chemical Germicides

Raw Materials

Sub-lethal Sterilization,

 

USP/CTFA Microbial Limits

 

Screen/FDA Manual

Water and ion exchange beds*

Filtration, UV Light, Sanitization

 

of Cationic and Anionic beds

Personnel

Hygiene, Training, Gowning,

 

Motion Restriction

*Gram negative bacilli (Pseudomonas, Enterobacter,Aeromonas, Klebsiella, Serratia, etc.) predominate, the opposite of the gram positive surface per­sistence in table I

2. Chapter 1111. "Microbiological Quality of Non-sterile Products". This informational chapter depends heavily upon chapters 61 and 62 and is not harmonized. It has some important additions: the term "objectionable" is removed and methods for yeast and mold count have been added for oromucosal, gingival, gingival cutaneous (mucocuta­neous), nasal, auricular, vaginal, inhalation and transder­mal dosage forms. Also, oral preparations have been sepa­rated into liquid/solid based on different acceptance crite­ria for anhydrous vs. aqueous products.

3. Chapter 1116. "Microbiological Evaluation of Clean Room and Other Controlled Environment." This important chap­ter covers the following subjects: aseptic processing of bulk substances, dosage forms, certain medical devices and microbial content of the manufacturing environment. Guidance is also provided on clean room classification, Federal Standard 209E, training of personnel, microbial environmental control programs, establishing sampling plans and sites, frequency of sampling in critical areas, alert and action levels, and a discussion of air samplers. Alert and action levels are defined. Certain important teaching is obtained from USP informational chapters. They can be list­ed as follows:

1. There is no scientific agreement on the relationship between non-viable particulates (as used in classification of air) and viable counts.

2. Microbial sampling should occur during normal operation and with personnel and materials within area.

3. Microbial monitoring of clean rooms and other controlled area should include air, compressed air, surfaces, equipment, sanitization containers, walls, floors, gowns and gloves.

Table 7, 8 and 9 are attributed to USP Chapter 1116

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MICROBIOLOGY

Table 7 Suggested Frequency of Sampling on the basis of Criticality of Controlled Environment (Based on USP Chapter 1116 Aseptic Fill Operations)

AreaTo Be Sampled

Schedule of Sampling*

Class 100 or Better

Each Operating Shift

Area Immediately Adjacent to

Each Operating Shift

Class 100 area (e.g. class 10,000)

Other Support Areas

Twice per Week

Potential Product/Container

Contact Areas

Twice per Week

Other Areas Supporting

Aseptic Process Area

Once per Week

* =Air, surfaces, Personnel

Viruses are unlikely in the controlled environment, unless shed by personnel. The only likely human reservoir would be respi­ratory virions shed from the throat or nasal droplets, especial­ly from talking, coughing and sneezing, and excessive body movement, from personnel unaware of barrier limitations for these very small organisms. Viruses most likely to be shed are:

A. Respiratory

1. Lipophilic (enveloped) 2.          Influenza A, B, C

3. Measles 4. RSV

5. MUMPS

6. German Measles

B. Partially Lipid Adenoviruses

Table 8 With respect to air sampling, air cleanliness guidelines have been suggested by USP in chapter I 116,

Class S.I.

U.S. Customary

cfu/cubic meter

cfu/cubic foot

M3.5

100

Less than 3

Less than 0.1

M5.5

10,000

Less then 20

Less than 0.5

M6.5

100,000

Less than 100

Less than 2.5

Table 9 Surface Cleanliness For Controlled Environments, USP 1116

cfu per contact plate

Class (U.S.)

Equipment &

Personnel

 

Facility

 

100

3 includes floor

Gloves 3

 

 

Clothing/garb 5

10,000

5, but floor= 10

Gloves 10

 

 

Clothing 20

Surface sampling should be conducted at the conclusion of operations. Swabs or contact plates may be used and incubat­ed with culture conditions as specified in company SOP or with specific reference to the USP guidelines, which are informa­tional only. With respect to microbial identification, an appro­priate knowledge of genus and species is valuable in (a) deter­mining trends and shifts, (b) evaluating the effectiveness of cleaning and sanitizing treatments, and (c) investigating sources of contamination. The pathogenicity of environmental isolates is left to medical authorities, but the term "adulter­ation" in the FDA sense is not limited to pathogens.

Viruses in Contamination Control

The question of contamination control arises on the presence of or inactivation of viruses in the manufacturing environment, or on the detection of these agents in the USP Sterility Test, espe­cially for articles sterilized by membrane filtration. There is no virus that we know of today that can withstand the 10-6 SAL terminal process of steam, ethylene oxide or irradiation.

C. Hydrophilic (naked)

1. Rhinoviruses (more than 100) common cold 2. Coxsackie viruses

3. ECHO viruses

D. Mucotaneous Dermal 1. Herpes 1

2. Herpes 2 3. Vaccinia (after Prince and Prince, Block, 2001)

The life cycle of viruses in human infections teaches that the greatest amount of aerosol shedding frequently occurs before signs and symptoms. If you are uncertain of the health status of a worker and the possibility of vectoring these agents to critical areas and surfaces, one can take either of two approaches: (1) do nothing and allow normal die-off as described in the desic­cation kinetics in Table 3, or (2) quickly apply 3, 5, or 10% fresh hydrogen peroxide solution, depending if you wish complete inactivation in 10, 5 or 2 seconds for a lipid virus (influenza). If you suspect a partially lipophilic virus (adenovirus) or naked hydrophilic agent (IZhinovirus), choose fresh 5% hydrogen per­oxide solution and apply for at least 30 seconds (Gibraltar Laboratories, unpublished data) The hydrogen peroxide will turn to sterile water and nascent oxygen, which can be wiped away. Do not use any other chemical germicide (quaternary, phenolic, aldehyde, iodophor, etc.) because this represents a needless contamination with extraneous organic matter. If you choose alcohol make sure it is sterile and a mixture of ethanol and isopropanol 50:50. All of the aforementioned is as much directed to regulatory and legal personnel within the firm as for scientific personnel, for consumer complaints about virus infections occur from time to time (herpes from lipstick or ster­ile catheters, AIDS virus from a vaccine, polio from water for injection and a scientific defense is possible). Viruses can nei­ther survive nor replicate in or on inanimate materials.

Summary

In this article, we have presented some concepts and experi­mental data on the existence and persistence of certain bacteria, yeasts and molds and viruses and how they may be controlled

6        CONTRACT PHARMA -June 2005

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by disinfectants, HEPA filtration and training of personnel. We have presented pertinent USP documents, such as USP 6, USP 18 and USP 27.

It cannot be stressed more strongly that USP informational chapters are for guidance only and are not necessarily obliga­tory for any firm. Recognizing the fluidity and changes in methods and standards that is part of the biological process, USP administers a well-organized program of revision. USP actively solicits feedback from the "consumer" pharmaceutical scientist and publishes the highly-valued Pharmacoepial Forum publications. Special attention must be paid to these in­process documents. When a USP official states that it is the Pharma community as a whole that is responsible for the con­tents of the Official and Informational chapters of USP, he is correct. Further, it is to be stressed that microbial content val­ues published in USP are not verified by any one standard of experimental data. We are not aware of any data from any firm that correlates action levels with product failure in terms of microbial content. The important thing is that surface, air and personnel counts are measurable and reproducible. What can­not be measured cannot be changed. What cannot be changed cannot be improved. When the constant search for improve­ment ends, quality becomes more difficult to maintain and complacency is inevitable. We dare not go back to the days of Prof. Kallings. •

About the Authors

Dr. Herbert N. Prince received his Doctorate at the University of Connecticut and AB degree at New York University. Before starting Gibraltar Laboratories he was an Assistant Research Director. In Microbiology and Toxicology at Hoffmann-LaRoche, Inc. He started his career as a Clinical Microbiologist in the New York City Health Department, was a member of the U.S. Army Medical Department and has taught at Seton Hall and Fairleigh Dickinson Universities.

Dr. Daniel L. Prince received his Doctorate in Microbiology and Molecular Biology at the Rutgers Medical School, New Brunswick. and AB degree at Clark University. He was a Research Microbiologist and Electron Micro­scopist at the Osborn Laboratory of Marine Sciences, Brooklyn, NY and has served on committees at USP and ASTM. He has given papers at FDA and PDA conferences and has numerous , publications in Research and Regulatory Microbiology, In Vitro Toxicology, and Antimicrobial Agents

 

REFERENCES

I. USP 6th Edition 1940 Epitome of the U.S. Pharmacopeia, American Medical Association, Robert Hatcher, M.D. et al., Chicago

2. USP XVIII 1970 United States Pharmacopeial Convention, Mack Publishing, Easton, Pa.

3. USP 27 2005 USP Convention, Rockland, Md.

4. Bruch, C. 1971 Cosmetics: Sterility vs. Microbial Control. Paper presented 10th International Industrial Pharmacy Seminar, Univ. Texas, Austin, 25 Feb. 1971.

5.   Kramer, J. 1974 U.S. Food and Drug Administration, Personal Communication on Parenteral Sterility.

6. Silver, K., Meacham, J. Kleks,A. 1971-1974 U.S. Food and Drug Administration, District Laboratories, Brooklyn, NY, personal communications

7.   Kallings, L.W., Ernerfeldt, F and Silverstolpe, L. 1965 Microbiological Contamination of Medical Preparations, Report to the Swedish Board of Health, Stockholm.

8. Kallings, L.W 1966 Further Studies on Contamination of Eye Ointments with Pseudomonas aeruginosa,Acta Pharma. Suecica 3:219.

9. Morse, L.J. et al 1967 Klebsiella Septicemia from Lanolin Hand Cream Dispenser New England Journal Medicine, 277:427 10. Production, Hygiene and Bacteriological Control in the Manufacture of Pharmaceuticals, Publication No. 115, Swedish National Board of Health, 1967.

11. Dunnigan,A.P and Evans. J.R. 1970 FDA Papers 4:10 Pharmaceutical and Cosmetic Contamination.

12. Prince, H.N. 1983 Disinfectant Activity Against Bacteria and Viruses:A Hospital Guide, Particulate and Microbial Control, Canon Communications.

13. Prince, H.N. and Rubino, J. 1984 Bioburden Dynamics:The Viability of Microorganisms on Devices Before and After Sterilization, Medical Device and Diagnostic Industry, Canon Communications.

14. Prince, H.N. and Prince, D.L. 2001 Principals of Viral Control and Transmission, in Disinfection, Sterilization and Preservation, S. Block ed., Lippincott Williams and Wilkins, Philadelphia.

15. Getchell-White, S.I. et al. 1989 The Inanimate Environment of an Intensive Care Unit AsA Potential Source of Infection of Nonsocomial Bacteria, Infection Control and Hospital Epidemiology 10:402

16.Saunders, FT 2001 Regulation of Antimicrobial Pesticides in The United States, in Disinfection, Sterilization and Preservation. S. Block ed., Lippincott Williams and Wilkins, Philadelphia.

17. Prince, H.N. and Prince, D.L. 2003 Antimicrobial Principles and Studies With Disinfectants and Antiseptics, Paper presented joint Meeting New Jersey Branches American Society Microbiology and Society Industrial Microbiology, 19 February 2003, Cook­Douglas Campus, Rutgers University, New Brunswick.

18. Prince, D.L. 2004 Alternative to chapter 61 Microbial Limit Test, Finger Lakes Fall Forum, October 13-15, 2004.

19. Porter, D.A 2005 USP Issues and Updates, paper presented 15 February 2005, N.J. Pharmaceutical Quality Control Association, Union, N.J.

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