PROJECT_237_2007_NAIR.KANERIA_D.S_MICRONIZATION

Sonam Kaneria, Deepa NairPAS 237 Industrial Pharmacy,

Fall 2007,

Pre Test QuestionCurrent 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)Controlled2)Robust3)Both

Objectives

Introduction

1)Factors affecting micronization

2)Why micronization is done?

Critical problems

Drug Recall

Case study

Conclusion

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.

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.

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

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.

Factors Affecting Micronization

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.

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.

Cont’d4.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

Critical ProblemsCompany- CIPLAProduct 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

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

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Case study: Warning letter1) 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

reviews.5)To thoroughly investigate out of specification results.

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

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

Post Seminar QuestionIs Quality by Design (QbD) approach, a solution, to

overcome the problems encountered during micronization and thereby make the process more robust ?

..