The document discusses the micronization process in the pharmaceutical industry, highlighting its objectives, factors influencing the process, and case studies of drug recalls due to micronization issues. It emphasizes the importance of controlling particle size to improve bioavailability and outlines critical problems faced by companies, including the need for regulatory compliance. A survey conducted at several universities indicated support for proposed solutions to enhance micronization effectiveness and quality assurance.

1. PROJECT_237_2007_NAIR.KANERIA_D.S_MICRONIZATION
Sonam Kaneria, Deepa Nair
PAS 237 Industrial Pharmacy,
Fall 2007,

2. Pre Test Question
Current recipe approach for micronization process
involves Time, Temperature, Humidity set as
predefined ranges. It is a fixed process; almost any
changes requires Agency approval. Do you think this
approach is –
1)Controlled
2)Robust
3)Both

3. Objectives
Introduction
1)Factors affecting micronization
2)Why micronization is done?
Critical problems
Drug Recall
Case study
Conclusion

4. Objective
To understand the nature of the process (ie;micronization)
by studying the factors affecting the process, the drug
recalls and critical problems associated with the
micronization.
To hypothesize a solution, by understanding the factors
leading to regulatory non-compliance of a unit operation
(micronization), from the selected 483.

5.  Micronization is defined as a process of reducing the
average diameter of a solid particle.
 Usually micronization term is used when the particle
that are produced only a few micrometers in diameter.
 In Pharmaceutical Industry the modern application
requires average particle diameter to be in nanometer
scale.
 Micronization has advantages of better bioavailability
assay for less soluble drugs, i.e.; for most of the
hydrophobic drugs e.g.; Chloramphenicol palmitate B.

6. Increased Dissolution Rate and Bioavalibilty through Comicronization with
Microcrystalline Cellulose .
Ref:-
http://www.informaworld.com/smpp/content~content=a725712792~d
b=all~order=page

7. Factors affecting Micronization
process
1)The properties of solid i.e. the resistance it offers to
undergo size reduction.
2)The equipment used for micronization has its own
influence on micronization.
Thus the product specifications along with the
equipment selected has a profound effect on the very
unit operation.

8. Factors Affecting Micronization

9. Why Micronization is done?
The effects of micronization are as follows:-
1)To increase the surface area per unit weight (i.e.; specific
surface).
2)To increase the dissolution rate.
 3)To increase the bioavailability.
The above three factors are the common
reasons for micronizing the drug particles.

10. Cont’d
The specific reasons pertaining to individual drugs include
few of the many:-
1.Control of particle size influences the duration of
adequate serum concentration, rheology and product
syringeability of a suspension of penicillin G procaine for
intramuscular injection.
2.The rectal absorption of aspirin from a theobroma oil
suppository is related to particle size.
3.Increased antiseptic action in calomel ointment when
the particle size of calomel has been reduced.

11. Cont’d
4.The size of particle used in inhalation aerosols
determines the position and retention of the particles in
bronchopulmonary system.
5.Extraction or leaching from crude vegetable drugs is
facilitated by comminution
6.Rapid filtration rates are observed in case of solutions.
7.Drying of wet masses is facilitated by micronization.
8.Micronization and subsequent drying increase the
stability because the occluded solvent is removed.
9.Micronization of ointments, pastes and creams provide a
smooth texture and better appearance in addition to
improved physical stability.
Ref :-Lachman pg 21- 22

12. Critical Problems
Company- CIPLA
Product Name-Endogest- contains micronized
progesterone soft and hard gelatin capsules, BP-200mg.
Micronized Progesterone is structurally and biologically
active.
 Micronization increases the bioavailability of the drug.
Critical problem encountered is that ‘Micronized
progesterone is devoid of estrogenic, androgenic and
mineralocorticoid effects’.
POSSIBLE REASONS: Probably the extreme reduction in
particle had led to the development of hydrophobic
charges eventually due to reduction in the surface area. 12

13. PRODUCT -Xactdose Phenytoin Oral Suspension,USP, 100mg/4 ml unit
dose cups, Category:- anticonvulsant.
CODE:- Recall #D-217-6.
Lot numbers: 508608 and 508613 EXP 2/97.
MANUFACTURER:- Parke-Davis, Division of Warner-Lambert
Company, Morris Plains, New Jersey.
RECALLED BY:- Xactdose, Inc., South Beloit, Illinois
(repacked), by letter dated July16,1996. Firm-initiated
recall ongoing.
DISTRIBUTION:- Nationwide. 1,947 cases were distributed;
QUANTITY 15% of the product remained on the market at time
of recall initiation.
REASON :- Due to large particle size, some of the unit doses may not
meet potency specifications.
REF:- http://www.fda.gov/ohrms/dockets/ac/00/slides/3609s1x.pdf
13

14. letter1) FDA issued a 483 to a leading pharmaceutical company for
failing to comply with cGMP regulations governing manufacturing
equipment used in Micronization.
“Failure to qualify manufacturing equipment such as the liquid
filler, homogenizer and colloidal mill, which were used to
manufacture all liquid finished products at your facility [21 CFR
211.68(a)].”
Ref:--http://www.fda.gov/foi/warning_letters/s6357c.htm
According to you which kind of strategies or corrective actions
should be followed by the company?: (Pl select the 2 most
appropriate corrective actions.)
1)A full review of all lots within expiration in the market to assure
that the released drug products have their appropriate identity,
strength, quality, and purity.
2)To validate the reprocessing procedure and the extent of the
validation.
3)To recall the drug from the market.
4)To provide written procedures for conducting periodic product

15. Graph:-
Based on the responses we have received a chart was prepared
which showed that maximum number of people agreed with the
hypothesized solution a) and the hypothesized solution b) came
second.( The survey was carried out in the University of Toledo,
University of Campbell, University of Houston Texas and
University of Boston. We achieved the results by mailing them
the survey questionnaire.)
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
a b c d e
Series1
Series2

16. Conclusion
The given case study along with the suggested strategies,
signify the need to improve upon the causes for poor
performance, and designing processes for continuous
feedback
control to reduce variability and non-compliance in
Micronization process.

17. Post Seminar Question
Is Quality by Design (QbD) approach, a solution, to
overcome the problems encountered during
micronization and thereby make the process more
robust ?

18. .
.