Confusion in Date of Manufacturing & Expiry for Ready to Fill Pellets in Capsules & Powder in Unit Dosage Form Injections

1. Confusion in Date of Manufacturing & Expiry
for Ready to Fill Pellets in Capsules & Powder in
Unit Dosage Form Injections
Roohi B. Obaid
Civil Service Officer/Deputy Director
At Drug Regulatory Authority of Pakistan
26 Nov 2016
2nd Annual Forum on Culture of Quality 2016
Habib University, Karachi
Disclaimer:
It is written and judged in the best of author's professional knowledge, experience and education.
It has nothing to do with the organization or societies to which author is associated, so there is
no obligation to the author's organization or societies on the document. It represents current
thinking of the author on the subject. Within the boundary of good science, critical thinking and
comment with reference will always be respected
Narrowing the Confusions and promote discussions based on science

2. Confusion in Date of Manufacturing & Expiry for Ready to Fill Pellets in Capsules & Powder in Unit Dosage Form Injections etc.
Page 2 of 4 Roohi B. Obaid Nov 26th, 2016
Confusion in Date of Manufacturing & Expiry for Ready to Fill Pellets in Capsules &
Powder in Unit Dosage Form Injections etc.
It is referring to the title indicated above. Going back to the issue, it appears that
haziness and hesitation are yet prevailing regarding the date of manufacturing and date of expiry
of filling of powders (Drug Substance) from bulk container to unit dosage forms (Drug Product)
and bulk liquids (Drug Substance) for unit packaging (Drug Product). Confusion on the subject
prevails and discussed a lot in a number of meetings and seminars.
2. Lets try to concentrate, re-think and narrate something in simple, extempore and original
words based on best of the knowledge, interpretation ability and professional experience. This
long continued practice is not only causing financial loss but also telltales the weakness in area
available for debate and discussion. Here it is attempted to describe and unfold the issues in a
simple and clear language.
I. Fundamental Descriptions:
a. Date of Manufacturing: In simple words it is a date (day) when first substance
comes in contact with the second substance, and this starts the manufacturing
process. As a matter of practice, month is used all around not the day for e.g.
April 2015 means 01 to 30 April 2015.
b. Date of Expiry: It is the date (day) when any drug (substance or product etc.) is
not allowed to be used, it is calculated on the basis of stability studies in particular
container closure system at different environmental conditions. Date of expiry
indicates life of product if stored in defined storage conditions. As a matter of
practice, month is used all around not the day for e.g. April 2018 means 30 April
2018.
c. Retest Date: This practice is limited to those drug substances that are studied
accordingly to demonstrate that the quality attributes translate its therapeutic
activity within acceptable limits of safety. It is the date (day) when substance is
required to go for extensive testing and upon compliance of quality attributes, its
life is extended in same container closure and environmental conditions of storage

3. Confusion in Date of Manufacturing & Expiry for Ready to Fill Pellets in Capsules & Powder in Unit Dosage Form Injections etc.
Page 3 of 4 Roohi B. Obaid Nov 26th, 2016
for a minimum period usually a month. This approach is not applicable to finished
products. As a matter of practice, month is used all around not the day for e.g.
April 2018 means 30 April 2018.
II. Issues with Recommendations:
a. Issue A; (Drugs Imported in Pellet Form): Pellets (Processed Material)
containing Drug Substance and excipients are imported for encapsulation or
suspensions to make final dosage form (Finished Drug Product). These pellets are
not manufactured in the finished dosage form manufacturing facility. Hence, as a
matter of applying best knowledge, the manufacturing date of this finished dosage
form starts when first material comes in contact with other material for the
manufacturing of pellets. The expiry date of encapsulated and suspension etc
finished dosage form is independent of the expiry date (shelf life) of Drug
Substance and likewise expiry date of pellets, because the container closure
system plays a vital and critical role in stability of the product. Therefore, without
conducting independent stability studies, the shelf life of the finished drug product
or pellets or drug substance cannot be determined. For. e.g. Omepraozole is
imported in pellets form and encapsulated in capsules of 20 mg and 40 mg.
Moreover, assumptions does not work unless not established on the basis of
scientific principles, so, an independent stability study of finished product is
required that may increase or decrease the shelf life compared to the shelf life of
the pellets.
b. Issue B; (Drugs Imported in Lyophilized/ Sterile Powder Form including
pre-mixed Sterile Powders): Bulk Drug Substances in powder form, in their
approved container closure system are used for manufacturing of finished drug
product. In this case, the manufacturing process is very simple and this bulk drug
substance is filled in small unit dosage form, without any process or addition of
any other substance. Since, the container closure system of the unit dosage form is
different, therefore, independent stability study is required to calculate shelf life
of the drug product. Furthermore, filling date of the bulk drug substance into unit

4. Confusion in Date of Manufacturing & Expiry for Ready to Fill Pellets in Capsules & Powder in Unit Dosage Form Injections etc.
Page 4 of 4 Roohi B. Obaid Nov 26th, 2016
dosage forms will be considered the most appropriate as the date of
manufacturing because nothing has come into contact with the drug substance.
For e.g. the Bulk Drug Substance Ceftriaxone Sodium to be filled in 250 mg,
500mg and 1000 mg vials respectively.
c. Issue C; (Import in Bulk & Local Repackaging): Bulk Drug Substances in
liquid form, in their approved container closure system are used for
manufacturing of finished drug product. In this case, the manufacturing process is
simple and consists of filling the bulk liquid in small unit packaging, without any
process or addition of any other substance. Since, the container closure system of
the unit dosage form is different, therefore, independent stability study is required
to calculate shelf life of the drug product. The filling date of bulk liquid is
considered the most appropriate as date of manufacturing because there is no
addition in the bulk liquid drug substance. For e.g. Lactulose bulk liquid is filled
into small unit packaging of 60 ml, 120 ml and 240 ml bottles respectively.
3. This is written with the sincere intent to strengthen the regulatory process with current
knowledge of good science and invite discussion/ technical input to unfold the subject. In this
way, encouragement of evolving good science to deal such issues in a consistent and uniform
manner will be developed. Last but not the least, the greater body of modern science is totally
concerned with truth. Science has never been more necessary than today, nor less sufficient; in
the future it will become more and more necessary, and more and more insufficient.
4. It is well understood that the capacity of improvement is always vacant; hence, all critical
comments, communications and counter arguments will not only be welcomed but highly
appreciated.