Hall_Quality of Misoprostol

Quality of misoprostol products

Asia Regional Meeting on Interventions for Impact

in Essential Obstetric and Newborn Care:

Prevention and Management of

Postpartum Hemorrhage and Pre-eclampsia/Eclampsia

and Special Care for Newborns

Dhaka, Bangladesh, 4-6 May 2012

Peter Hall, Chief Executive Officer,

Concept Foundation, Bangkok and Geneva

• Study on quality of misoprostol products

• Factors influencing quality

• What is being done to address issues

• Implications for procurement

Prevention and Management of Postpartum Hemorrhage and

Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012

Product availability

• Searle (now part of Pfizer), registered misoprostol,

as Cytotec, worldwide (except for most sub-

Saharan African countries) for the prevention

of gastric ulcers associated with NSAIDs.

• Misoprostol is widely available as generic

formulations and, in many countries, cheaply.

• Has begun to be registered for obstetric

indications in various countries.

• Included on WHO Model List of Essential Medicines

for induction of labour; incomplete abortion; with

mifepristone for early abortion; and for prevention of PPH.



Product availability

• In 2009, Ipas estimated are some 50

manufacturers of misoprostol worldwide.

• In India are some 30 brands of misoprostol and 10

brands of combination packs of mifepristone and

misoprostol; are several contract manufacturers

giving at least 16 FPP manufacturers;

• Are at least 20 brands in other lower and middle

income countries, excluding China and S Korea.

Because of proliferation of products, Gynuity Health

Projects funded Concept Foundation to undertake a

study on quality of misoprostol FPPs.



Study on misoprostol content and purity

Samples collected

- 76 samples collected from Argentina,

Bangladesh, Cambodia, Egypt, Kenya, India,

Mexico, Nigeria, Pakistan, Peru and Viet Nam.

(30 from India, 23 from other Asian countries,

14 from Africa and 9 from Latin America).

Samples analyzed

- 2 excluded which included diclofenac;

- 74 analyzed for content, 58 for impurities.



Misoprostol content by age

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

110%

120%

130%

0 200 400 600 800 1000 1200 1400 1600 1800 2000

Mis

op

rosto

l co

nte

nt

(%L

A)

Time (days)



Results on content and purity

• 34 out of 74 samples tested had content less than 90% of labelled content; 8 had less than 20%.

• One year from manufacture, 19 out of 31 samples tested had content less than 90% of labelled content; 7 had less than 20%.

• The content of some products appear to decrease between 3 months and one year.

• 31 out of 58 samples tested had impurities > EP/USP limits, 18 > 2x EP/USP limits.



0%

20%

40%

60%

80%

100%

120%

140%

472

610

771

245

741

113

238

384

1931

50

223

277

476

499

Time (days)

Mis

op

ros

tol C

on

ten

t (%

LA

)API

2 3 4 Manufacturer

A B B B/C ?/?

1 5/6

Package alu-alu alu-alu alu-alu plastic-alu plastic-alu

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

100.00%

110.00%

120.00%

130.00%

0 200 400 600 800 1000 1200 1400 1600 1800 2000

Time (days)

Mis

op

ro

sto

l co

nten

t (

%L

A)

Plastic-Alu

Alu-Alu

C

A

B

Misoprostol study - overall conclusions

• Results show significant problems with certain

misoprostol finished products when analyzed

for content and purity.

• With a few products, misoprostol appears to

degrade rapidly between 3 months and one

year (these would not have been detected by

preshipment QC!).

But there are quality products that do not

deteriorate with time.



Factors influencing quality

The quality of a misoprostol FPP is impacted by:

• the API - how it was manufactured: whether

manufacture meets current Good Manufacturing

Practices (CGMP); and how it is stored;

• the manufacturing process of the finished

product - whether it meets CGMP; whether

adequate environmental controls instituted

during manufacturing process; and conditions

under which the finished product is stored;

• the type of packaging used.



Addressing these issues

Results discussed with several of the principal

manufacturers of misoprostol FPPs

Evidence that appropriate environmental control

at all stages of manufacturing process and use of

a double aluminium blister pack will prevent

degradation of the finished product.

With API is of proven quality and appropriate

quality assurance procedures established,

manufacturers can make quality FPPs.




Possible

PQ by end

of 2013

Potential

for PQ by

2015

Not very

interested

Unlikely to

achieve

PQ

5 2-3 3 3

Concept has visited 14 companies and concluded:



In the absence of prequalified products, UNFPA has

instituted an interim process for product review by a

new Expert Review Panel for RH Medicines to be

undertaken by WHO. Manufacturers must demonstrate

adequate compliance with GMP and a commitment to

continue to prequalification. Up to 5 products could

complete this process in 2-6 months.


Concept is:

• Working with VSI on a manual on best practices

and technical information for finished product

manufacturers. Draft about to be made available.

• Working with two API manufacturers to get

misoprostol dispersion prequalified by WHO.

• Providing technical assistance to selected

manufacturers for to meet CGMP and submit

appropriate documentation first to the new

ERP/RHM and then to WHO’s PQ Programme



Implications for procurement

• To obtain products of assured quality, it must be

understood that quality cannot be assessed, tested or

inspected in finished products - quality must be built in!

• WHO prequalification helps minimize risk and allows

procurers greater confidence in their risk management

strategies. Concept is aiming for 4 FPPs prequalified

by end of 2013.

• Meantime, in order to reduce risk and avoid duplication

of effort, procurers should work towards a harmonized

procurement and quality assurance strategy that

acknowledges the following issues.



Implications for procurement

Preshipment testing may be of little value for

inappropriately manufactured and packaged

product.

Procurers must ensure that misoprostol FPPs are

sourced from a manufacturer that can demonstrate:

• API and excipients are of proven quality,

supported by a DMF

• FPP is manufactured under CGMP and

appropriate environmental controls

• FPP is packed in a double aluminium blister pack



Hall_Quality of Misoprostol

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