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Chapter 2. Postapproval Changes to Semisolid Drugs

Chapter 2. Postapproval Changes to Semisolid Drugs

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18



Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products



E.

F.



Change in the technical grade of structureforming excipient

Change in particle size distribution of the drug

substance if the drug is in suspension



Definition of level 3 changes are those that are likely to

have a significant effect on formulation quality and performance. Examples:

A. Any qualitative and quantitative changes in an

excipient beyond the ranges noted in level 2

change.

B. Change in crystalline form of the drug substance, if the drug is in suspension



I.



PRESERVATIVE



For semisolid products, any change in the preservative

may affect the quality of the product. If any quantitative

or qualitative changes are made in the formulation, additional testing should be performed. No in vitro release

documentation or in vivo bioequivalence documentation

is needed for preservative changes.



changes should be properly validated and may be inspected

by appropriate agency personnel. Level 1 changes in batch

size are those up to and including a factor of 10 times the

size of the pivotal clinical trial or biobatch, where the

equipment used to produce the test batch or batches is of

the same design and operating principles, the batch or

batches are manufactured in full compliance with current

good manufacturing practice (CGMPs), and the same standard operating procedures (SOPs) and controls, as well as

the same formulation and manufacturing procedures, are

used on the test batch or batches and on the full-scale

production batch or batches. Level 2 changes in batch size

are those from beyond a factor of 10 times the size of the

pivotal clinical trial or biobatch, where the equipment used

to produce the test batch or batches is of the same design

and operating principles, the batch or batches is manufactured in full compliance with CGMPs, and the same SOPs

and controls, as well as the same formulation and manufacturing procedures, are used on the test batch or batches

and on the full-scale production batch or batches. No level

3 changes are anticipated in this category.



IV.

II.



MANUFACTURING CHANGES



Manufacturing changes may affect both equipment used

in the manufacturing process and the process itself. A level

1 change is a change from nonautomated or nonmechanical equipment to automated or mechanical equipment to

transfer ingredients or a change to alternative equipment

of the same design and operating principles. A level 2

change is a change in equipment to a different design or

different operating principles or a change in type of mixing

equipment, such as high shear to low shear and vice versa.

No level 3 changes are anticipated in this category.



III.



PROCESS



Level 1 changes include changes such as rate of mixing,

mixing times, operating speeds, and holding times within

approved application ranges, in addition to the order of

addition of components (excluding actives) to either the

oil or water phase. Level 2 changes include changes such

as rate of mixing, mixing times, rate of cooling, operating

speeds, and holding times outside approved application

ranges for all dosage forms in addition to any changes in

the process of combining the phases. No level 3 changes

are anticipated in this category.

Batch Size (Scale Up or Down)

The minimum batch size for the NDA pivotal clinical trial

batch or the ANDA/AADA biobatch is at least 100 kg or

10% of a production batch, whichever is larger. All scale



© 2004 by CRC Press LLC



MANUFACTURING SITE



Manufacturing site changes consist of changes in location

in the site of manufacture, packaging and filling operations, or testing for both company-owned and contract

manufacturing facilities, and they do not include any other

level 2 or 3 changes; for example, changes in scale, manufacturing (including process or equipment), and components or composition. New manufacturing locations

should have had a satisfactory CGMP inspection within

the past 2 years. A stand-alone analytical testing laboratory site change may be submitted as a Changes Being

Effected Supplement if the new facility has a current and

satisfactory CGMP compliance profile with the FDA for

the type of testing operation in question. The supplement

should contain a commitment to use the same test methods

employed in the approved application, written certification

from the testing laboratory stating that they are in conformance with CGMPs, and a full description of the testing to be performed by the testing lab. If the facility has

not received a satisfactory CGMP inspection for the type

of testing involved, a prior approval supplement is recommended. No stability data are needed for a change in a

stand-alone analytical facility. Level 1 changes consist of

site changes within a single facility where the same equipment, SOPs, environmental conditions (e.g., temperature

and humidity) and controls, and personnel common to

both manufacturing sites are used, and where no changes

are made to the manufacturing batch records, except for

administrative information and the location of the facility.

“Common” is defined as employees already working on the

campus who have suitable experience with the manufacturing



Postapproval Changes to Semisolid Drugs



process. Level 2 changes consist of site changes within a

contiguous campus, or between facilities in adjacent city

blocks, where similar equipment, SOPs, environmental

conditions (e.g., temperature and humidity) and controls,

and personnel common to both manufacturing sites are

used, and where no changes are made to the manufacturing

batch records, except for administrative information and

the location of the facility. Level 3 changes consist of a

site change in manufacturing site to a different campus.

A different campus is defined as one that is not on the



© 2004 by CRC Press LLC



19



same original contiguous site or where the facilities are

not in adjacent city blocks. To qualify as a level 3 change,

similar equipment, SOPs, environmental conditions, and

controls should be used in the manufacturing process at

the new site. Changes should not be made to the manufacturing batch records except when consistent with other

level 1 changes. Administrative information, location, and

language translation may be revised as needed. Any

change to a new contract manufacturer also constitutes a

level 3 change.



3



Scale-Up and Postapproval

Changes for Nonsterile

Semisolid Dosage Forms:

Manufacturing Equipment

I.



INTRODUCTION



Any equipment changes should be validated in accordance

with current good manufacturing practices (CGMPs). The

resulting data will be subject to examination by field investigators during routine GMP inspections. The information

here is presented in broad categories of unit operation

(particle size reduction or separation, mixing, emulsification, deaeration, transfer, and packaging).

Under scale-up and postapproval changes (semisolid) (SUPAC-SS), equipment within the same class and

subclass are considered to have the same design and

operating principle. For example, a change from a planetary mixer from manufacturer A to another planetary

mixer from manufacturer B would not represent a change

in design or operating principle and would be considered

the same.

A change from equipment in one class to equipment

in a different class would usually be considered a change

in design and operating principle. For example, a change

from a planetary mixer to a dispersator mixer demonstrates a change in operating principle from low-shear

convection mixing to high-shear convection mixing. These

types of equipment would be considered different under

SUPAC-SS.

Applicants should carefully consider and evaluate on

a case-by-case basis changes in equipment that are in

the same class but different subclasses. In many situations, these changes in equipment would be considered

similar. For example, in Section III, Mixing, under the

convection mixers, low shear, a change from an impeller

mixer (subclass) to a planetary mixer (subclass) represents a change within a class and between subclasses.

Provided the manufacturing process with the new equipment is validated, this change would likely not need a

Changes Being Effected (CBE) Supplement. At the time

of such a change the applicant should have available the

scientific data and rationale used to make this determination. It is up to the applicant to determine the filing

category.



© 2004 by CRC Press LLC



II.



PARTICLE SIZE REDUCTION

AND SEPARATION



A. DEFINITIONS

1.



Unit Operations



a. Particle Size Reduction

Particle size reduction is the mechanical process of breaking particles into smaller pieces via one or more sizereduction mechanisms. The mechanical process used is

generally referred to as milling.

i.



Particle



A particle is either a discrete crystal or a grouping of

crystals, generally known as an agglomerate.

ii.



Particle Size Reduction Mechanisms

















Impact—Particle size reduction caused by applying an instantaneous force perpendicular to the

particle or agglomerate surface; the force can

result from particle-to-particle or particle-to-mill

surface collision

Attrition—Particle size reduction by applying

force parallel to the particle surface

Compression—Particle size reduction by applying

a force slowly (as compared with impact) to the

particle surface toward the center of the particle

Cutting—Particle size reduction by applying a

shearing force to a material



b. Particle Separation

Particle separation is particle size classification according

to particle size alone.

2.



Operating Principles



a. Fluid Energy Milling

Fluid energy milling is particle size reduction by highspeed particle-to-particle impact or attrition (also known

as micronizing).



22



Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products



b. Impact Milling

Particle size reduction by high-speed mechanical impact

or impact with other particles (also known as milling,

pulverizing, or comminuting) is known as impact milling.

c. Cutting

Cutting is particle size reduction by mechanical shearing.

d. Compression Milling

Particle size reduction by compression stress and shear

between two surfaces is known as compression milling.

e. Screening

Particle size reduction by mechanically induced attrition

through a screen (commonly referred to as milling or

deagglomeration) is called screening.

f.

Tumble Milling

Tumble milling is particle size reduction by attrition, using

grinding media.



4.



Compression Mills



Although compression mills, also known as roller mills,

can differ in whether one or both surfaces move, no compression mill subclasses have been identified.

5.



Screening Mills



Screening mill subclasses primarily differ in the rotating

element.







6.



Oscillating bar

Rotating impeller

Rotating screen

Tumbling Mills



Tumbling mill subclasses primarily differ in the grinding

media used and whether the mill is vibrated.









Ball media

Rod media

Vibrating



g. Separating

Particle segregation based on size alone, without any significant particle size reduction (commonly referred to as

screening or bolting), is also known as separating.



7.



B.



EQUIPMENT CLASSIFICATIONS



Separator subclasses primarily differ in the mechanical

means used to induce particle movement.



1.



Fluid Energy Mills



Fluid energy mill subclasses have no moving parts and

primarily differ in the configuration or shape of their

chambers, nozzles, and classifiers.

















Fixed target

Fluidized bed

Loop or oval

Moving target

Opposed jet

Opposed jet with dynamic classifier

Tangential jet









Impact Mills



Impact mill subclasses primarily differ in the configuration of the grinding heads, chamber grinding liners (if

any), and classifiers.









3.



Cage

Hammer air swept

Hammer conventional

Pin or disc

Cutting Mills



Although cutting mills can differ in whether the knives

are movable or fixed, and in classifier configuration, no

cutting mill subclasses have been identified.



© 2004 by CRC Press LLC



Centrifugal

Vibratory or shaker



Please note that if a single piece of equipment is capable

of performing multiple discrete unit operations, it has been

evaluated solely for its ability to affect particle size or

separation.



III.



MIXING



A. DEFINITIONS

1.



2.



Separators



Unit Operation



Mixing is the reorientation of particles relative to one

another to achieve uniformity or randomness. This process

can include wetting of solids by a liquid phase, dispersion

of discrete particles, or deagglomeration into a continuous

phase. Heating and cooling via indirect conduction may

be used in this operation to facilitate phase mixing or

stabilization.

2.



Operating Principles



a. Convection Mixing, Low Shear

Convection mixing, low shear, is a mixing process with a

repeated pattern of cycling material from top to bottom in

which dispersion occurs under low power per unit mass

through rotating low shear forces.



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