STANDAR PROSEDUR TEKNIKASEPTIK DAN

SAFE HANDLING CYTOTOXICWORKSHOP SAFE HANDLING OF CYTOTOXIC DRUGS

L. ENDANG BUDIARTI

Injections Aqueous bronchial inhalations Baths and soaks for live organs andtissues Irrigations for internal body cavities(i.e., any space that does not freelycommunicate with the environmentoutside of the body) Ophthalmics Implants

CERTAIN PHARMACEUTICAL PRODUCTS MUST BESTERILE

TWO CATEGORIES OF STERILE PRODUCTS

those that can be sterilized infinal container (terminally

sterilized)

those that cannot be terminallysterilized and must beaseptically prepared

Aseptic processing

• Objective is to maintain the sterility of aproduct, assembled from sterile components

• Operating conditions so as to prevent microbialcontamination

COMPOUNDED STERILE PREPARATIONS (CSPS)USP 797 (REVISED 2015 USP 39 PAGE 626

• Scope : to all persons who prepare CSPs (e.g., pharmacists,pharmacy technicians, physicians, veterinarians, and nurses)at all places where CSPs are prepared (e.g., hospitals andother healthcare institutions, patient treatment sites, infusionfacilities, pharmacies, and physicians’ or veterinarians’practice sites).

MAJOR EDITS TO THE CHAPTER INCLUDE

1. Collapsed compounded sterile preparations (CSP) microbial risk categories fromthree to two and changed terminology. No sterile compounding is inherently “lowrisk” .

- Category 1 CSPs have a shorter beyond use date (BUD) and may be prepared ina segregated compounding area;

- Category 2 CSPs have a longer BUD and must be prepared in a cleanroomenvironment.

2. Removed specific information on handling of hazardous drugs and addedreferences to Hazardous Drugs—Handling in Healthcare Settings 800ۧۦ .

3. Introduced terminology for “in-use time” : CSP must be used after it has beenopened or punctured.

COMPOUNDED STERILE PREPARATIONS (CSPS)USP 797 (REVISED 2015)

1) microbial contamination (nonsterility),

2) excessive bacterial endotoxins,

3) variability from the intended strength of correct ingredients,

4) chemical and physical contaminants,

5) use of ingredients of inappropriate quality.

to prevent harm including death

TYPES OF CONTAMINATION

• ParticulateDust, skin, hair, make up…

• ChemicalOil, grease, metal ions, perfume…

• BiologicalBacteria, fungi, rodents???

• RadiationUltraviolet light…

PARTICLE CHARACTERISTICS

• 50 micron particles are visible

• Average human hair is about 100 microns

• Time to fall 1 meter in still air

• 33 seconds for 10 micron particle

• 48 minutes for 1 micron particle

• Humans generate >1x105 particles per minute when motionless (fullygowned)

• Humans can generate >1x106 particles when walking in the cleanroom

10

WHY ALL THE CONCERN ABOUT DUST?

Typical size relationship between

dust, bacteria and viruses

Virus

(0,006µm to 0,03µm)

Dust Particle

(0,5µm to 500µm)

Bacteria

(0,2µm to 2µm)

Dust Is a Bacteria Carrier

WHO

11

Particle sizes

AIRBORNE CONTAMINANTS

WHO

Co

nta

min

ati

on

rate

Filling chronology (time or units)

ContaminationContamination

Contamination rate increasing during filling

This could indicate acontamination originated in theliquid media path (i.e. wrongaseptic connection to the mediatank, contamination in therecirculation loop).

It is important to keep underaseptic conditions the mediabulk tank at the end of filling,while waiting the media fillresults, for verifying thishypothesis

CONTAMINATION CONTROL

• Personnel Control

• Dress code

• Personal Hygiene

• Gowning

• Environmental Control

• Entrance and exit

• Materials and supplies

• Cleaning and maintenance

• Atmospheric

• People ~75%

• Ventilation ~15%

• Room Structure ~5%

• Equipment ~5%

CONTAMINATION SOURCES

SPECIFIC ISSUES RELATING TO THE MANUFACTURE OFASEPTICALLY PREPARED PRODUCTS:

• Manufacturing environment

• Clean areas

• Personnel

• Preparation and filtration of solutions

• Pre-filtration bioburden

• Filter integrity/validation

• Equipment/container preparation and sterilization

• Filling Process

• Validation of aseptic processes

• Specific issues relating to Isolators, BFS and Bulk

MANUFACTURING ENVIRONMENT

Classification of Clean Areas

• Classified in terms of airborne particles (Table 2)

Grade At rest In operation

maximum permitted number of particles/m3

0.5 - 5.0 µm > 5 µm 0.5 - 5.0 µm > 5 µ

A 3 500 0 3 500 0

B 3 500 0 350 000 2 000

C 350 000 2 000 3 500 000 20 000

D 3 500 000 20 000 not defined not defined

“At rest” - production equipment installed and operating

“In operation” - Installed equipment functioning in definedoperating mode and specified number of personnel present

PREPARATION

SYRINGE

NEVER TOUCH

Tip or Plunger

CARA MEMINIMALKAN KONTAMINASI

Menghilangkan / membunuh micro organisme dari tangan hand washing

Menghilangkan / membunuh micro organisme dari objek swab objek, desinfeksi

Membuat steril alat yang akan digunakan

Mengurangi resiko terpapar micro organisme AlatPelindung Diri

KEBERSIHAN TANGAN

Cuci tangan 6 langkah

Prosedur terpenting untuk mencegah transmisipenyebab infeksi (orang ke orang; objek ke orang)

Antiseptik, dan air mengalir

Bukti :cuci tangan menunjang penurunaninsiden MRSA di ICU

RISK FACTOR

Batch size

Complexity of the compounding process

(e.g., number of manipulations involved; whether starting with nonsterileor sterile components)

Inherent nature of the drug being compounded

(e.g., whether the drug is susceptible to microbial growth; whether thepreparation will be preservative free)

Complexity of the compounding operation

(e.g., multiple people in the cleanroom at the same time; multiple CSPsbeing prepared at the same time; activity in the surrounding areas)

Length of time between the start of compounding

(including making a stock solution) and administration of the drug to thepatient

RISK FACTOR

Pharmacy Compounding–USP <797>Risk Level Assessment

Risk Category Requirements, Guidance & Examples

Immediate-Use

•For emergent use, or situations where low-riskcompounding would add risk due to delays•No storage or batch compounding•Continuous compounding process lasting less than one hour•Aseptic technique utilized•Administer less than 1 hour after preparation begins, ordiscard•Simple transfer of sterile nonhazardous drugs or diagnosticradiopharmaceuticals

Low-Risk Level

•Simple admixtures compounded using closed systemtransfer methods•Prepared in ISO Class 5 LAFW•Located in ISO Class 7 buffer area with ISO Class 8ante area•Examples include reconstitution of single-dose vials ofantibiotics or other small-volume parenterals,preparation of hydration solutions

Low-Risk Level with <12 Hour BeyondUse Date

•Simple admixtures compounded usingclosed system transfer methods•Prepared in ISO Class 5 PEC•Compounding area is segregated fromnon-compounding areas•Administration must start no laterthan 12 hours after preparation

Medium-Risk Level

•Admixtures compounded using multiple additivesand/or small volumes•Batch preparations (e.g., syringes)•Complex manipulations (e.g., TPN)•Preparation for use over several days•Prepared in ISO Class 5•Located in ISO Class 7 buffer area with ISO Class 8ante area•Examples include pooled admixtures, parenteralnutrition solutions using automated compounders,batch-compounded preparations that do not containbacteriostatic components

High-Risk Level

•Non-sterile (bulk powders) ingredients•Open system transfers•Prepared in ISO Class 5•Located in ISO Class 7 buffer area with separate ISOClass 8 ante area•Examples include CSPs prepared from bulk, nonsterilecomponents or final containers that are nonsterile andmust be terminally sterilized

Beyond Use Dates

Risk CategoryRoom

TemperatureRefrigeration Frozen (≤10 °C )

Immediate-Use 1 hour 1 hour N/A

Low-Risk 48 hours 14 days 45 days

Low-Risk with 12-hour BUD

12 hours 12 hours N/A

Medium-Risk 30 hour 9 days 45 days

High-Risk 24 hours 3 days 45 days

LABEL

Labels for single compounded preparations must, at a minimum, include thefollowing:- Names of active ingredients,- Amounts or concentrations of active ingredients- BUD and time,- Storage requirements, and- Identification of responsible compounding personnel.- Labels for batch-prepared

CSPs must also include:- Control or lot number,- Appropriate auxiliary labeling (including precautions), and- Device-specific instructions (when appropriate).

THE JOINT COMMISSION VIEW IS THAT ALTHOUGHSURVEYED IN THE PHARMACY, THESE NEW REQUIREMENTSWILL BE JUDGED IN THE FOLLOWING EC STANDARDS

• Environment design of drug preparation rooms (EC.8.10)

• Air quality testing and environmental monitoring of compoundingenvironment (EC.7.10 testing), (EC.9.10 monitoring)

• Temperature testing of drug storage areas (EC.6.10)

• Automated compounding device—verification of accuracy, calibrationand maintenance (EC.6.10)

IDENTIFIKASI, ASESMEN DAN PENGENDALIAN RISIKODALAM PROSES DISPENSING SITOSTATIKA

http://www.asia4safehandling.org/

DANGER

Antineoplastic agents are typically used as cancerchemotherapeutic agents.

Antineoplastic hazardous agents are genotoxic,teratogenic, carcinogenic, or toxic to other targetorgans even at very low concentrations

7 GROUP OF ANTINEOPLASTIC

Alkylating agents:

Alkylating agents undergo alkylation by a nucleophilic substitution reaction with cellularconstituents, such as DNA base pairs, cell membranes, proteins, and proteins.

Antitumor antibiotics:

The antitumor antibiotics are synthesized from microorganisms. The antitumorantibiotics either break-up DNA strands, slow, or stop DNA synthesis.

Antimetabolites:

Antimetabolites are structurally similar to metabolites required for normal biochemicalreactions. Antimetabolites interfere with cellular processes such as cell division.

7 GROUP OF ANTINEOPLASTIC

Nitrosoureas:

Nitrosoureas act similar to that of alkylating agents and slow down or stop enzymes that helprepair DNA.

Mitotic agents (plant alkaloids):

Plant alkaloids break DNA strands and prevent cell replication.

Hormonal agents:

Steroids lyse lymphoblasts and thus directly cause lymphoid malignancies.

Miscellaneous agents:

Though mechanisms of miscellaneous agents are not well understood, these agents probablyinhibit DNA, RNA, and protein synthesis.

PERSONAL PROTECTIVE EQUIPMENT (PPE)

TABLE 1. EXAMPLES OF POTENTIAL ROUTES OF EXPOSURE BASED ON ACTIVITY

Activity Potential Route of ExposureDispensing Counting tablets and capsules from bulk containers

Compounding Crushing tablets or opening capsules

Pouring oral or topical liquids from one container to another

Weighing or mixing components

Constituting or reconstituting powdered or lyophilized HDs

Withdrawing or diluting injectable HDs from parenteral containers

Expelling air or HDs from syringes

Contacting HD residue present on PPE or other garments

Deactivating, decontaminating, cleaning, and disinfecting areas contaminated with or suspected to be contaminated

with HDs Maintenance activities for potentially contaminated equipment and devices

Administration Generating aerosols during administration of HDs by various routes (e.g. injection, irrigation, oral, inhalation, or topical

application)

Performing certain specialized procedures (e.g., intraoperative intraperitoneal injection or bladder instillation)

Priming an IV administration set

Patient-care activities Handling body fluids (e.g., urine, feces, sweat, or vomit) or body-fluid-contaminated clothing, dressings, linens, and

other

Spills Spill generation, management, and disposal

Receipt Contacting with HD residues present on drug container, individual dosage units, outer containers, work surfaces, or

floors

Transport Moving HDs within a healthcare setting

SCOPE

1. Responsibilities of PersonnelHandling Hazardous Drugs

2. Facilities

3. Environmental Quality and Control

4. Personal Protective Equipment

5. Hazard Communication Program

6. Personnel Training

7. Receiving

8. Labeling, Packaging, and Transport

9. Dispensing Final Dosage Forms

10.Compounding

11.Administering

12.Deactivation/Decontamination,Cleaning, and Disinfection

13. Spill Control

14. Disposal

15. Documentation and StandardOperating Procedures

16. Medical Surveillance

PERSONNEL

All personnel who handle HDs are responsible for :

• understanding the fundamental practices and precautions

• continually evaluating these procedures and the quality of final HDs toprevent harm to patients,

• minimize exposure to personnel,

• minimize contamination of the work and care environment.

• TRAINING - UPDATED

FACILITIES

CLEAN ROOM

CYTOTOXIC SAFETY CABINET

LABELTRANSPORTATION

PERSONAL PROTECTIVE EQUIPMENT (PPE)

Double glovesNitril/latexchemo

N95 : maskerEye protection andface shield

DECONTAMINATION

• At a minimum, all contaminated (and potentially contaminated)work surfaces should be cleaned with detergent solutionfollowed by several rinses with clean water.

SPILL MANAGEMENT – ENVIRONMENT, CARE GIVERPROTECTION

A N95, R95, P95 dust mask, or moreprotective half/full face respiratorsshould be worn during an antineoplasticdrug spill cleanup.

WASTE DISPOSAL

• All materials contaminated with antineoplastic agents must bedisposed of as hazardous chemical waste.

• Antineoplastic drug waste solids and solutions : contained separately

• Outer gloves and sleeve covers : collected with antineoplastic drugcontaminated laboratory waste.

• Containerize the waste : in a plastic bag, double bag; seal the bag andplace in a hard-sided sealable plastic container. Label and seal the boxfor disposal.

• Needles and syringes : in sharps container, also for disposal ashazardous chemical waste.

• The outside of antineoplastic agent waste containers must be cleanedand free of contamination for disposal

• A written SOP for safe handling of antineoplastic agents should include:

• laboratory staff training,

• PPE,

• receiving and storage,

• labeling,

• preparation and manipulation of antineoplastic agents in physicochemical studies oranimals,

• equipment used,

• housekeeping practices,

• glassware decontamination,

• spill cleanup, and disposal of antineoplastic agents as hazardous waste.

• SOPs for handling different forms of antineoplastic agents (i.e. tablet, injectable liquid,etc.) should also include anticipated

GUIDELINES - ORAL CYTOTOXIC

i. safe prescribing of oral chemotherapy agents

ii. safe handling of chemotherapy agents

iii. safe administration of chemotherapy agents

iv. safe disposal of cytotoxic waste

Worksafe Victoria, Jan 2003, Handling cytotoxic Drugs in the Workplace

Prescribing, pharmacist and nurses who has the appropriate training and skills incancer chemotherapy

R/ Dispensing

compounding administering monitoring InformasiEdukasi

Dokter Keputusan terapi,BSA/BBPembulatandosis, jml/cycle

Efek terapi, ESOSemua profesisesuai SPO

Patologi, indikasi,pengobatan

Apoteker Verifikasiresep,label

VPerubahanbentuk sediaan

Stop, missed dose ESO Pengobatan, efek ygtdk diinginkanTertulis, verbal

Perawat vTdk menumbuk,memotongtablet

Hindari : kontakkulit· lepasnya serbukdi udara· kontaminsai dgnobat lain

ESO suporting

Pasien x

ORAL CYTOTOXIC

· All layers : of the packaging must be clearly marked ascytotoxic including the outer bag that contains thesupply

· The container should offer protection from the lightwhere required.

- Where cytotoxic medication is supplied in glass

bottles then a pharmacist must confirm whetherother containers are suitable for dispensing orwhether it is essential that the glass bottle be used toavoid any adverse affects on the drug

6/1/2016

· If a blister pack is used,- this must be filled by the pharmacist dispensing the

chemotherapy and- labeled with relevant instructions with a cytotoxic warning

label.- Other non cytotoxic medication MUST NOT be placed into the

same pack

· Oral chemotherapy agents should be stored:- as directed by the pharmacist,- in a secure manner,- out of the reach of children

· Tablet containers should have child proof caps. Where this isnot the case, care should be taken to ensure that they arekept out of the reach of children

LIMBAH

• Semua sisa obat kembali ke farmasi pemusnahan (Any unused medication should be returned to thepharmacy for appropriate disposal)

• Incenerator 1100C

• Limbah kering:

• Sarung tangan, plastik tempat obat, syringe, wadah obat (blister, botol, plastik)

• Linen basah terkontaminasi:

• Sprei, sarung bantal, baju, handuk

• Urine, vomits, blood, sperm and other bodily fluids

• 7 hari sejak menggunakan kemoterapifull flush with the lid down

• Permukaan terkontaminasi segera dibersihkan dengan air dan detergent

(Contaminated surfaces should be washed with copious amounts of water and with detergen)

• Transport limbah dari rumah ke rumah sakit : wadah tdk mudah pecah/robek dlm plastik ungu, terikatkuat

Remember to thoroughly wash hands uponcommencement and completion of disposing ofdrugs contaminated products and waste

MARI DISKUSI