FDA外用制剂检查指南

GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS

Note: This document is reference material for investigators and other FDA

personnel. The document does not bind FDA, and does no confer any rights,

privileges, benefits, or immunities for or on any person(s).

I. PURPOSE

The purpose of this guide is to provide field investigators, who are

familiar with the provisions of the Current Good Manufacturing Practice

(CGMP) regulations for pharmaceuticals, with guidance on inspecting selected

facets of topical drug product production. The subjects covered in the guide

are generally applicable to all forms of topical drug products, including

those that are intended to be sterile. However, this guide does not address

every problem area that the investigator may encounter, nor every policy

that pertains to topical drug products.

II. INTRODUCTION

This inspectional guide addresses several problem areas that may be

encountered in the production of topical drug products potency, active

ingredient uniformity, physical characteristics, microbial purity and

chemical purity. The guide also addresses problems relating to the growing

number of transdermal products. If a new drug pre-approval inspection is

being conducted, then an examination of the filed manufacturing and control

data, and correspondence should be accomplished early in the inspection. As

with other pre- approval inspections, the manufacturing and controls

information filed in the relevant application should be compared with the

data used for clinical batches and for production (validation) batches.

Filed production control data should be specific and complete.

III. POTENCY UNIFORMITY

Active ingredient solubility and particle size are generally important

ingredient characteristics that need to be controlled to assure potency

uniformity in many topical drug products such as emulsions, creams and

ointments. Crystalline form is also important where the active ingredient is

dispersed as a solid phase in either the oil or water phase of an emulsion,

cream, or ointment.

It is important that active ingredient solubility in the carrier vehicle be

known and quantified at the manufacturing step in which the ingredient is

added to the liquid phase. The inspection should determine if the

manufacturer has data on such solubility and how that data was considered by

the firm in validating the process.

Substances which are very soluble, as is frequently the case with ointments,

would be expected to present less of a problem than if the drug substance

were to be suspended, as is the case with creams. If the drug substance is

soluble, then potency uniformity would be based largely upon adequate

distribution of the component throughout the mix.

If the active ingredient is insoluble in the vehicle, then in addition to

assuring uniformity of distribution in the mix, potency uniformity depends

upon control of particle size, and use of a validated mixing process.

Particle size can also affect the activity of the drug substance because the

smaller the particle size the greater its surface area, which may influence

its activity. Particle size also affects the degree to which the product may

be physically irritating when applied; generally, smaller particles are less

irritating.

Production controls should be implemented that account for the solubility

characteristics of the drug substance; inadequate controls can adversely

affect product potency, efficacy and safety. For example, in one instance,

residual water remaining in the manufacturing vessel, used to produce an

ophthalmic ointment, resulted in partial solubilization and subsequent

recrystallization of the drug substance; the substance recrystallized in a

larger particle size than expected and thereby raised questions about the

product efficacy.

In addition to ingredient solubility/particle size, the inspection should

include a review of other physical characteristics and specifications for

both ingredients and finished products.

IV. EQUIPMENT AND PRODUCTION CONTROL

Mixers

There are many different kinds of mixers used in the manufacture of topical

products. It is important that the design of a given mixer is appropriate

for the type of topical product being mixed. One important aspect of mixer

design is how well the internal walls of the mixer are scraped during the

mixing process. This can present some problems with stainless steel mixers

because scraper blades should be flexible enough to remove interior

material, yet not rigid enough to damage the mixer itself. Generally, good

design of a stainless steel mixer includes blades which are made of some

hard plastic, such as teflon, which facilitates scrapping of the mixer walls

without damaging the mixer.

If the internal walls of the mixer are not adequately scraped during mixing,

and the residual material becomes part of the batch, the result may be

non-uniformity. Such non-uniformity may occur, for example, if operators use

hand held spatulas to scrape the walls of the mixer.

Another mixer design concern is the presence of

quantities of the formula are stationary and not subject to mixing. Where

such

recirculation or non-use of the cream or ointment removed from the dead

spots in the tank.

Ideally, during the inspection, mixers should be observed under operating

conditions.

Filling and Packaging

Suspension products often require constant mixing of the bulk suspension

during filling to maintain uniformity. When inspecting a suspension

manufacturing process determine how the firm assures that the product

remains homogeneous during the filling process and audit the data that

supports the adequacy of the firm's process. When the batch size is large

and the bulk suspension is in large tanks, determine how the firm deals with

low levels of bulk suspension near the end of the filling process. Does the

bulk suspension drop below a level where it can be adequately mixed? Is

residual material transferred to a smaller tank? Does the firm rely upon

hand mixing of the residual material? The firm should have demonstrated the

adequacy of the process for dealing with residual material.

Process Temperature Control

Typically, heat is applied in the manufacture of topicals to facilitate

mixing and/or filling operations. Heat may also be generated by the action

of high energy mixers. It is important to control the temperature within

specified parameters, not only to facilitate those operations, but also to

assure that product stability is not adversely affected. Excessive

temperatures may cause physical and/or chemical degradation of the drug

product, vehicle, the active ingredient(s), and/or preservatives.

Furthermore, excessive temperatures may cause insoluble ingredients to

dissolve, reprecipitate, or change particle size or crystalline form.

Temperature control is also important where microbial quality of the product

is a concern. The processing of topicals at higher temperatures can destroy

some of the objectionable microorganisms that may be present. However,

elevated temperatures may also promote incubation of microorganisms.

Temperature uniformity within a mixer should be controlled. In addressing

temperature uniformity, firms should consider the complex interaction among

vat size, mixer speed, blade design, viscosity of the contents and the rate

of heat transfer. Where temperature control is critical, use of recording

thermometers to continuously monitor/document temperature measurements is

preferred to frequent manual checks. Where temperature control is not

critical, it may be adequate to manually monitor/document temperatures

periodically by use of hand held thermometers.

V. CLEANING VALIDATION

It is CGMP for a manufacturer to establish and follow written SOPs to clean

production equipment in a manner that precludes contamination of current and

future batches. This is especially critical where contamination may present

direct safety concerns, as with a potent drug, such as a steroid (e.g.,

cortisone, and estrogen), antibiotic, or a sulfa drug where there are

hypersensitivity concerns.

The insolubility of some excipients and active substances used in the

manufacture of topicals makes some equipment, such as mixing vessels, pipes

and plastic hoses, difficult to clean. Often, piping and transfer lines are

inaccessible to direct physical cleaning. Some firms address this problem by

dedicating lines and hoses to specific products or product classes.

It is therefore important that the following considerations be adequately

addressed in a firm's cleaning validation protocol and in the procedures

that are established for production batches.

Detailed Cleaning Procedures

Cleaning procedures should be detailed and provide specific understandable

instructions. The procedure should identify equipment, cleaning method(s),

solvents/detergents approved for use, inspection/release mechanisms, and

documentation. For some of the more complex systems, such as clean-in-place

(CIP) systems, it is usually necessary to provide a level of detail that

includes drawings, and provision to label valves. The time that may elapse

from completion of a manufacturing operation to initiation of equipment

cleaning should also be stated where excessive delay may affect the adequacy

of the established cleaning procedure. For example, residual product may dry

and become more difficult to clean.

Sampling Plan For Contaminants

As part of the validation of the cleaning method, the cleaned surface is

sampled for the presence of residues. Sampling should be by an appropriate

method, selected based on factors such as equipment and solubility of

idues. For example, representative swabbing of surfaces is often used,

especially in hard to clean areas and/or where the residue is relatively

insoluble. Analysis of rinse solutions for residues has also been shown to

be of value where the residue is soluble and/or difficult to access for

direct swabbing. Both methods are useful when there is a direct measurement

of the residual substance. However, it is unacceptable to test rinse

solutions (such as purified water) for conformance to the purity

specifications for those solutions, instead of testing directly for the

presence of possible residues.

Equipment Residue Limits

Because of improved technology, analytical methods are becoming much more

sensitive and capable of determining very low levels of residues. Thus, it

is important that a firm establish appropriate limits on levels of

post-equipment cleaning residues. Such limits must be safe, practical,

achievable, verifiable and must ensure that residues remaining in the

equipment will not cause the quality of subsequent batches to be altered

beyond established product specifications. During inspections, the rationale

for residue limits should be reviewed.

Because surface residues will not be uniform, it should be recognized that a

detected residue level may not represent the maximum amount that may be

present. This is particularly true when surface sampling by swabs is

performed on equipment.

VI. MICROBIOLOGICAL

CONTROLS (NON-STERILE

TOPICALS)