Asia Regional Meeting on Interventions for Impact in Essential Obstetric and Newborn Care Dhaka, Bangladesh May 3-6,

6, 2012

Quality of Oxytocin Injections: a Case Study in Indonesia

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

Outline of Presentation
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

Overview of the Project

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

Background and Rationale

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 - continued

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

Made with good quality Oxytocin

Chemical Structure of Oxytocin Mwt- 1007.2

Pharmacopeial Specifications for Storage Temperature

Currently USP, BP, JP, WHO Ph. Int. have monographs for dosage forms; EP has no dosage forms monograph
Monograph API Injection USP 35 BP 2012 JP 15
2 - 8 C Cold place

Ph. Int. 4th Edn.

2 - 8 C 2 - 8 C unless otherwise indicated on the label

7th

EP Edition

Refrigerated 2 - 8 C Not specified Not specified

2 - 8 C No monograph available

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.

Temperature Stability Recommendations

WHO recommends storage under refrigeration (2C - 8C) as much as possible.1

It is acceptable to keep oxytocin injections unrefrigerated for short periods: 30C not exceeding one month, or 40C 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 30C storage conditions

IDA Foundation study performed in collaboration with WHO recommended to store refrigerated.2
At 2C - 8C: Below 21C: At 25C: At 30C: At 40C: 3 year shelf life 2 year shelf life 1 year shelf life 6 months shelf life Maximum 1 week

1. 2.

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) 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

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. 2. 3. 4. 5.

Papua regiondistrict of Mimika Aceh regiondistrict of Bireun West Java regiondistrict of Cianjur East Kalimantan regiondistrict of Kutai Timur Banten regiondistrict of Pandeglang and Tangerang

Study Sites From which Samples were Collected

Oxytocin Injections to be Collected

Major commercial and generic brands of synthetic injectable oxytocin were collected at sampling locations. These included:
Induxin

Oxytocin
Pitoqin

Synthocinon

Quality Testing at the NIHRD and NQCL-DF

Samples of oxytocin injections were analyzed using USP33NF28 Reissue specifications for:

Correct labeling and packaging

Product name, strength, volume/quantity Route of administration Mfg date and/or expiry date Manufacturers name and address Storage condition requirements

Organoleptic examination for contaminant or strange particle matters Identification of oxytocin API Assay for content of oxytocin API

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%

Number of samples collected by level of service

Level of service Province PHO Aceh Banten West Java East Kalimantan Papua Total 1(5.6%) 0 (0%) 2 (8.7%) DHO 3 (16.7%) 2 (5.4%) 4 (17.4%) PHC 3 (16.7%) 6 (16.2%) 3 (13.0%) MWC 11 (61.1%) 29 (78.4%) 14 (60.9%) 18 (100%) 37 (100%) 23 (100%) Total

0 (0%) 3 (16.7%)

2 (14.3%) 2 (11.1%)

3 (21.4%) 6 (33.3%)

9 (64.3%) 7 (38.9%) 70 (63.6%)

14 (100%) 18 (100%) 110 (100%)

6 (5.5%) 13 (11.8%) 21 (19.1%)

Failure rate of oxytocin injection samples by province

No

Site

sample passed quality testing 18 (100%) 35 (94.6%) 18 (78.3%) 10 (71.4%) 16 (88.9%)

sample failed quality testing 0 (0%) 2 (5.3%) 5 (21.7%) 4 (28.6) 2 (11.1%)

Total

1 2 3 4 5

Aceh Banten West Java East Kalimantan Papua

18 (100%) 37 (100%) 23 (100%) 14 (100%) 18 (100%)

Total

97 (88.2%)

13 (11.8%)

110 (100%)

Failure rate of oxytocin injection by level of service

No

Level of Service PHO DHO PHC MWC Total

sample passed the analysis 6 (100%) 13 (100%) 16 (76.2%) 62 (88.6%) 97 (88.2%)

sample failed the analysis 0 (0%) 0 (0%) 5 (23.8%) 8 (11.4%)

Total

1 2 3 4

6 (100%) 13 (100%) 21 (100%) 70 (100%)

13 (11.2%) 110 (100%)

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

Expiration date

Sample age by brand

Study limitations and constraints

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

Conclusions
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

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