Dr. Souly Phanouvong and Dr. Victor S. Pribluda, PQM, USP

Dr. Shirley Villadiego, PATH

Dr. Indri Rooslamiati, NIHRD, Indonesia

Ms. Ati Setiawati, NQCL-DF, Indonesia

Quality of Oxytocin Injections:

a Case Study in Indonesia

Asia Regional Meeting on Interventions for Impact in Essential Obstetric

and Newborn Care Dhaka, Bangladesh May 3-6, 2012

1. Project Overview, Background, and Rationale

2. Quality of oxytocin: Stability considerations

3. Study Objectives and Methodology

Sampling

Testing

Results

4. Study limitations and constraints

5. Conclusions

6. Lessons Learned

Outline of Presentation

Title: Assessment of the Quality of Oxytocin Injection in Ampoules in

Selected Provincial Health Offices, District Health Offices, Primary

Health Care Centers, and Village Midwife Clinics in Indonesia

Goal: Assess the quality (appearance, ID, and assay for API content) of

available oxytocin injections in ampoule samples randomly collected

Objectives: Identify constraints for storage of oxytocin injections that may affect

quality

Formulate recommendations for improvement

Project partners: Program for Appropriate Technology in Health (PATH)

Maternal and Child Health Integrated Program (MCHIP)

United States Pharmacopeia (USP)

National Institute of Health Research and Development (NIHRD)

National Quality Control Laboratory for Drug and Food (NQCL-DF)

Funded by USAID/Indonesia

Overview of the Project

Oxytocin Injection Indications

A survey1 in 2006 of active management of the third stage of labor in

Indonesia suggested that oxytocin was a medicine of choice for the

prevention of post-partum hemorrhage (PPH)

Oxytocin is included in the Indonesia National Essential Medicines

List

Oxytocin is widely available for prevention and treatment of PPH

The same survey found that in 22% of the facilities assessed,

health providers used greater than the recommended dose of

oxytocin because they did not think the medicine was providing

the expected effect.

1. Active Management of the Third Stage of Labor. Data obtained from health facilities in Indonesia 2006.

Available at: http://www.pphprevention.org/files/FINALIndonesiareport.pdf

Background and Rationale

Other considerations that prompted this study

Limited information available on how oxytocin injections are

stored at PHO, DHO, PHCC, and MWC levels

Quality assurance and quality control systems for oxytocin

injections during acquisition, transportation, and distribution

are also unknown

No post-marketing surveillance of their quality and efficacy is

in place

Background and Rationale - continued

Made with good quality Oxytocin

Chemical Structure of Oxytocin

Mwt- 1007.2

Monograph USP 35 BP 2012 JP 15 Ph. Int. 4th Edn.

EP 7th Edition

API Refrigerated 2 °- 8 °C 2 °- 8 °C 2 °- 8 °C 2 °- 8 °C

Injection Not specified

Not specified

Cold place

2 °- 8 °C unless

otherwise indicated on the label

No monograph available

Currently USP, BP, JP, WHO Ph. Int. have monographs

for dosage forms; EP has no dosage forms monograph

Not including cold storage requirements removes the

misconception that oxytocin is extremely unstable and

allows for following manufacturer recommendations, but

it could suggest that oxytocin is always stable at

controlled room temperature.

Pharmacopeial Specifications for Storage Temperature

WHO recommends storage under refrigeration (2°C - 8°C) as

much as possible.1 It is acceptable to keep oxytocin injections unrefrigerated for short

periods: 30°C not exceeding one month, or 40°C for two weeks

The same WHO report indicated no potency loss after 12 months of

refrigerated storage but a loss of between 9-19% potency under 30°C

storage conditions

IDA Foundation study performed in collaboration with WHO

recommended to store refrigerated.2 At 2°C - 8°C: 3 year shelf life

Below 21°C: 2 year shelf life

At 25°C: 1 year shelf life

At 30°C: 6 months shelf life

At 40°C: Maximum 1 week

1. WHO Action Programme on Essential Drugs and Vaccines. Stability of injectable oxytocics in tropical climates. 1993. Available at:

(http://apps.who.int/medicinedocs/pdf/s2205e/s2205e.pdf)

2. IDA Foundations. Simulation study stability Oxytocics. Michiel de Goeje. Stability data simulation study based on study performed in

collaboration with WHO WHO/DAP/93.6. Available at: http://www.pphprevention.org/files/Simulationstudyoxytocics_000.ppt

Temperature Stability Recommendations

Study Design and Methodology

This study uses simple, stratified, random sampling of different brands

and lots of oxytocin injections available at various levels of services:

PHO, DHO, PHCC and VMC in the following five regions:

1. Papua region–district of Mimika

2. Aceh region–district of Bireun

3. West Java region–district of Cianjur

4. East Kalimantan region–district of Kutai Timur

5. Banten region–district of Pandeglang and Tangerang

Study Sites From which Samples were Collected

Major commercial and generic brands of synthetic

injectable oxytocin were collected at sampling

locations. These included:

Induxin

Oxytocin “S”

Pitoqin

Synthocinon

Oxytocin Injections to be Collected

Samples of oxytocin injections were analyzed using USP33-

NF28 Reissue specifications for:

Correct labeling and packaging

Product name, strength, volume/quantity

Route of administration

Mfg date and/or expiry date

Manufacturer’s name and address

Storage condition requirements

Organoleptic examination for

contaminant or strange particle matters

Identification of oxytocin API

Assay for content of oxytocin API

Quality Testing at the NIHRD and NQCL-DF

Evaluation of Test Results

A sample was considered failed if its test results

did not conform with required specifications for any

one of the following:

Organoleptic test of contaminant or strange particle

matters

Identification

Assay of content of oxytocin API of 90.0%-110.0%

Province Level of service

Total PHO DHO PHC MWC

Aceh 1(5.6%) 3 (16.7%) 3 (16.7%) 11 (61.1%) 18 (100%)

Banten 0 (0%) 2 (5.4%) 6 (16.2%) 29 (78.4%) 37 (100%)

West Java 2 (8.7%) 4 (17.4%) 3 (13.0%) 14 (60.9%) 23 (100%)

East

Kalimantan 0 (0%) 2 (14.3%) 3 (21.4%) 9 (64.3%) 14 (100%)

Papua 3 (16.7%) 2 (11.1%) 6 (33.3%) 7 (38.9%) 18 (100%)

Total 6 (5.5%) 13 (11.8%) 21 (19.1%) 70 (63.6%) 110 (100%)

Number of samples collected by level of service

No Site sample passed

quality testing

sample failed

quality testing Total

1 Aceh 18 (100%) 0 (0%) 18 (100%)

2 Banten 35 (94.6%) 2 (5.3%) 37 (100%)

3 West Java 18 (78.3%) 5 (21.7%) 23 (100%)

4 East Kalimantan 10 (71.4%) 4 (28.6) 14 (100%)

5 Papua 16 (88.9%) 2 (11.1%) 18 (100%)

Total 97 (88.2%) 13 (11.8%) 110 (100%)

Failure rate of oxytocin injection samples by province

No Level of

Service

sample passed

the analysis

sample failed the

analysis Total

1 PHO 6 (100%) 0 (0%) 6 (100%)

2 DHO 13 (100%) 0 (0%) 13 (100%)

3 PHC 16 (76.2%) 5 (23.8%) 21 (100%)

4 MWC 62 (88.6%) 8 (11.4%) 70 (100%)

Total 97 (88.2%) 13 (11.2%) 110 (100%)

Failure rate of oxytocin injection by level of service

Storage conditions by level of service

API content of failed samples

QC results based on storage duration and conditions

QC results based on expiration date and sample age

Sample age by brand

Expiration date

Number of samples collected (110) did not meet objective of:

114 assuming a 5% failure rate

216 assuming a 10% failure rate

No of samples collected at initial sampling sites: 91

No of samples collected at expanded sites: 19

Sites with insufficient number of units to perform analytical tests

Time and budget affected

Number of samples and collection times

Type of tests performed:

Uniformity of dosage and microbiological tests

Study limitations and constraints

The overall 11.8% failure rate highlights a serious problem with

the quality of oxytocin injections at sampling sites

The study suggests a correlation between storage conditions and

failure rate

Failure rate for refrigerated samples:11.9%

Failure rate for non-refrigerated samples:15.8%

However, due to the limited number of samples a strong

correlation could not be established

Problems identified in QA systems

Storage in controlled environment is not a common practice

Lack of specific guidelines during transportation, supply, and

distribution

Results suggest problems in GMP

Conclusions

Lessons Learned

Buy-in of the government and active involvement of partners are key

to getting the project started and keeping it going

Constant communication and updates among partners are critical to

project progress and timely implementation

Well-prepared and organized training on sampling and testing should

be an integral part of the study

Limited availability of samples in the lowest level of use presented an

issue which required more time and resources by having to visit other

sampling locations

Uniformity of dosage units by API content should be included as one

of the quality testing parameters; also microbiological tests, whenever

there is a sufficient number of units.

For further questions on this study please contact Dr. Souly Phanouvong at:

SXP@usp.org

+1-301-816-8582

http://www.pqmusp.org