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

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

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

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.