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Installation, Operational, and Performance Qualification

Installation, Operational, and Performance Qualification

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Handbook of Pharmaceutical Formulations: Liquid Products

may render the premises unsuitable forever if proper validation could not be performed. For example, if a penicillin or cephalosporin product is manufactured on the premises, this premises can no longer be used for any other

product, as it would be difficult to prove the absence of




Site plan drawings should be available for facilities used

in clinical trial material production as well as for those at

which commercial products will be produced. These drawings quickly show how the facility is constructed and

controlled and include the floor plan, which shows the

proper segregation of areas by walls, airlocks, and doors;

these plans are useful to demonstrate people and equipment flow, showing that clean personnel and equipment

do not cross paths with dirty personnel and equipment.

Also, there should be a broader facility and grounds plan

showing the relative position and location of various buildings in the facility. This is particularly useful where multiple building are used to finish the product or to test it,

as the security of the batch in transit and the possibility

of contamination are key issues to be resolved. In addition,

drawings of the utility systems, such as the heating, ventilation, and air-conditioning systems and water systems,

should be available. Firms are advised that they may

request the FDA to review these drawings before the visit,

perhaps at the time of installation, to make sure that the

basic guidelines are adhered to.

strongly reminded that in most inspections the FDA finds

this to be one of the weakest areas. For example, some of

the common FDA citations for training violations include

lack of formal training documentation, lack of training in

GMP regulations on an ongoing basis, lack of a formal

job function training program, lack of a system for evaluating or monitoring employees to ensure that training

was effective, no provision for retraining individuals on a

periodic basis to ensure that employees remain familiar

with the requirements applicable to them, no provision for

training employees on recently revised procedures, and no

provision for ensuring that employees were trained before

they perform job functions. Training records should also

include details about how the new employees are trained

to follow the company’s SOPs, rules, and other regulations. The SOP reading and understanding records, therefore, form vital evidence that the FDA examines to ensure

that all employees have received adequate training in performing their tasks. Awareness and understanding of what

is considered critical depends on the role the employee

plays; for example, compliance with good laboratory

pratices (GLP) or good clinical practice may be relevant

to some, but not all, employees. Safety training, job function training, and documentation training are additional


10. Validation Records

Some of the most significant data that the PAI team confirm is the stability profile of the product; most likely the

raw data would be examined if the presentation of the

summary data appears flawed.

Validation protocols may include test parameters, product

characteristics, production equipment specifications and

settings, and decision points on what constitutes acceptable test results. Three types of validation protocols should

be available during the PAI: cleaning, manufacturing process, and analytical methods. Any data associated with a

completed protocol should also be made available. Also,

if there had been any retrospective validation, these data

should also be available.


11. Technology Transfer and Scale-Up


Stability Data


SOPs relevant to basic systems and operations should be

provided in a neatly arranged folder starting with the master validation plan, product, personnel, and process management. A comprehensive index should be attached.


Training Records

It is a cGMP requirement (21 CFR 211.25 a, b) that

personnel have education, training, or experience that

enables them to perform their assigned task. These training records should include the training curriculum for each

individual, as well as the list of completed courses. These

records should be made available for all personnel who

manufacture, process, package, test, or release clinical

trial materials and the commercial product. Firms are

© 2004 by CRC Press LLC

The goal of technology transfer and scale-up is to show,

through process control, that any modifications made from

conception to implementation have been appropriately

evaluated and documented and that the product is safe,

pure, and effective. The technology transfer master plan

comprises three components: the documents, the writing

style, and the illustration of equivalents. The development

stage documents are often abbreviated, and the files are

not necessarily as complete as in the case of full-scale

production; also in addition, the language used often differs as the audience changes from a scientist to a line

worker. It is important also to show how the equivalent

processes were selected; for example, when using a small

dryer, how can the use of large fluid bed dryer be labeled

as equivalent?

Preapproval Inspections


12. Quality Policy

13. Vendor Approval

The quality policy is a global document for the company

that covers such issues as recalls, employee training and

certification, and overall impact analysis of product and

process changes. Customer expectations, materials

specifications, and laws and regulations may also affect

the number of personnel needed and the way quality functions are subdivided into manageable work units. Of

importance for inclusion in the quality systems description

are the documenting controls, including clearance and

issuance of production records, procedures, specifications,

and so forth; internal and vendor audits; sampling, examination, and approval of materials, including packaging

and labeling (often administered by the laboratory component of the department); Material Review Board representatives; verifying yields and other critical production

data through production record audits; finished product

release; accompanying FDA investigators and external

auditors; administering or contributing to cGMP, safety,

or other required training programs; ensuring the investigations of product failures, process deviations, laboratory

out-of-specification findings, and consumer complaints;

monitoring approval and implementation of corrective

action plans and change controls; on-site verification of

the performance of critical production operations such as

clearing labeling equipment and lines; review and

approval of the product development records and documents transferring a product from development to commercial production; validation/qualification protocols and

summary reports acceptance; and annual cGMP review.

In addition, some functions are delegated to the engineering group to complete, and these include statistical process

control and trend analyses; calibration of instruments and

equipment, including out-of-specification follow-up; and

analysis of reports of extraordinary maintenance and preventative maintenance failures.

The ISO 9001 and ISO 9002 Quality Standards require

manufacturers to select vendors on the basis of their

ability to meet purchase specifications. By ISO 9004

definition, this includes meeting regulatory requirements

and safety standards. The FDA’s cGMP regulations 21

CFR 211.84(a) through (e) require a manufacturer to test

and approve or reject components, drug product containers, and closures. 21 CFR 211.84(d)(2) requires the manufacturer to test each component for conformity with

written specifications for purity, strength, and quality or

to accept the supplier’s report of analysis. 21 CFR

211.84(d)(3) requires the manufacturer to test containers

and closures for conformance with all appropriate written procedures or to accept the supplier’s report of analysis. Reports showing compliance with firm’s vendor

approval policy are required at the time of PAI.

© 2004 by CRC Press LLC

14. Outside Contractors

When any work is contracted out, whether in manufacture or testing phase, the FDA will hold the firm where

the deviation or deviations occurred responsible for violations of the cGMP regulations (21 CFR 210 and 211)

that pertain to those services. However, the contractor

and the application holder will be held jointly responsible for processes performed by the contractor to the

extent that each party contributed to the violations. Performance of each party will be considered in determining

whether one or both parties are subject to regulatory

action for failure to comply with cGMPs. It is in the best

interest of the applicant to perform due diligence in the

selection of any contractor, as well as to audit the contractors to ensure they meet the regulatory requirements

and the contractual commitments.


5 Formulation

of Liquid Products

Liquid formulations offer many advantages, from ease in

dosing to ease in administration (easy to swallow), and

myriad possibilities of innovative drug delivery systems.

One of the most desirable features of liquid formulations,

particularly the solution forms, is the relatively lower

importance of bioavailability considerations, as the drug

molecules are already in the dispersed phase, removing

many rate-limiting steps in the absorption of drugs. For the

purpose of this volume, liquid formulations include formulations that have liquid characteristics, meaning they can

flow and thus include clear liquids, suspensions, and extemporaneous powder suspensions (which could easily be classified as uncompressed solids but for the stability considerations postreconstitution, which are common to liquid

preparations). However, all of the advantages of liquid dosage forms are balanced by the many problems in their

formulation. These include stability problems, taste masking needs, phase separations, and so forth, all of which

require highly specialized formulation techniques.


The amount of active drug dissolved per unit of a solvent

or liquid base is a critical parameter subject to many

factors including temperature, presence of electrolytes

(salting-out effect), complexation with other components,

state of crystallinity (such as amorphous), nature of crystals (inclusion or imperfections), hydration, or salvation,

and so forth. One of the most important studies conducted

on new chemical entities is the solubility characteristics,

phase conversion studies, and saturation limits under different conditions. Where the amount of drug is above

saturation solubility, an equilibrium between the solution

(monomolecular dispersion) is established with undissolved particles (often multimolecular dispersions), the

direction and extent of which are governed by many physicochemical factors. Because the absorption of drugs takes

place only from a monomolecular dispersion (except those

instances of pinocytosis, etc.), the equilibrium of the two

states is critical to drug absorption. A large number of pHadjusting buffers are used in the liquid products to modify

the solubility of drugs as well as to provide the most

optimal pH for drug absorption and drug stability. The

dielectric constant of the solvent (or composite dispersion

phase) is important in determining the solubility. With

available values of dielectric constant available, for both

pure systems and binary systems, it is easy to project the

solubility characteristics of many new drugs. Another factor determining the solubility of drugs is the degree of

solubilization in the dispersion phase.

Solubilization is defined as spontaneous passage of

poorly water-soluble drugs into an aqueous solution of a

detergent, the mechanism being entrapment of drug molecules in the micelles of surface active agent. As a result,

many liquid preparations contain surfactants, not only to

solubilize but also to “wet” the powders to allow better

mixing with liquid phase. Because the critical micelle

concentration of surfactants is highly dependent on the

presence of other polar or dielectric molecules, the use of

surfactants to solubilized drugs requires extensive compatability studies. The most common solubilizers used

include polyoxyethylene sorbital, fatty acid esters, polyoxyethylene monoalklyl ethers, sucrose monoesters, lanolin esters and ethers, and so forth.

Complexation with other components of formulation

can give rise to enhanced or reduced solubility. Organic

compounds in solution generally tend to associate with

each other to some extent, but these are weak bonds, and

the complex readily disassociates. Where the drug forms

a stronger complex, such as with caffeine or other binders,

solubility can be extensively altered. Some polyols are

known to disrupt complexes, reducing the solubility. Often

complexation results in loss of active drug or a preservative used in the system, leading to serious stability problems. Examples of complexation include when xanthines,

polyvinyl pyrrolidone, and so on bind to drugs.

Hydrotrophy is defined as an increase in solubility in

water caused by presence of large amounts of additives.

It is another type of “solubilization,” except the solubilizing agent is not necessarily a surfactant. The phenomenon

is closer to complexation, but the change in solvent characteristics play a significant role as well. In general, the

quantity of other components must be in the range of 20

to 50% to induce hydrotrophy.


Many poorly soluble drugs can be made more water soluble by modifying their chemistry, such as introducing by

a hydrophilic group on the molecule. Salts and derivates

of poorly soluble drugs are widely used, and modification

requires a careful selection because different salts and


© 2004 by CRC Press LLC


Handbook of Pharmaceutical Formulations: Liquid Products

forms may not have the same chemical stability, and also

because the biologic activity may be modified.


Preservatives are almost always a part of liquid formulations unless there is sufficient preservative efficacy in the

formulation itself, such as due to high sugar content, presence of antimicrobial drugs, or solvents that inhibit growth

such as alcohol. In all instances a preservative efficacy

challenge is needed to prove adequate protection against

the growth of microorganisms during the shelf-life and

use of the product (such as in the case of reconstituted

powder suspensions). A large number of approved preservatives are available, including such universal preservatives as parabens, to protect liquid preparations. Among

the acidic group, the most prominent preservatives are

phenol, chlorocresol, O-pheyl phenol, alkyl esters of

parahydroxybenzoic acid, benzoic acid and its salts, boric

acid and its salts, and sorbic acid and its salts; neutral

preservatives include chlorbutanol, benzyl alcohol, and

beta-phenylethyl alcohol; mercurial preservatives include

thiomersal, phenylmercuric acetate, and nitrate; and

nitromersol and quarternary compounds include benzalkonium chloride and cetylpyridinium chloride. The admissible levels of preservatives are defined in the pharmacopoeia. It should be noted that although preservatives

provide an essential function, they often cause an unpleasant taste and allergic reactions in some individuals, requiring proper labeling of all products containing preservatives.


Because taste is of prime importance in the administration

of liquid products, sweetening agents ranging from sugar

to potassium acesulfame are widely used; appropriate

warnings are required when using artificial sweetening

agents. Often a combination of sweetening agents is used,

in combination with various flavors (which are often

included to make the product more palatable), to impart

the best taste. When formulating granules for dispersion,

solid flavors are preferred.

(DMF) for the purpose of filing regulatory applications. The

formulator is referred to Givaudan (http://www.

givaudan.com/), International Flavors and Fragrances

(http://www.iff.com), and Flavors of North America

(http://www.fonaflavors.com). Detailed information about

other companies can be obtained from the National Association of Flavor and Fragrances (http://www.naffs.org/

naffs/public/members.htm). It is noteworthy that as of the end

of 2003, all foreign manufacturers of flavors are required to

file a registration with the U.S. Food and Drug Administration

under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002.


Because the flow of liquid for dispensing and dosing is

important, an appropriate control of viscosity is required

to prevent the liquid from running and, at the same time,

to allow good dosing control; many thickening agents are

available including carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, and sugar. Because of the

significant opportunities available for interacting with

salts and other formulation ingredients, the viscosity control should be studied in the final formulation and over

the shelf life of the product.


The appearance or color of liquid products is often synchronized with the flavors used; for example green or blue

for mint, red for berry, and so forth. Because the amount

of dyestuffs allowed in pharmaceutical products is

strongly regulated, this presents problems — especially

where there is a need to mask features of a preparation.

In some instances, solutions are made to “sparkle” by

passing them through a filtration process. Often, adsorbents are used in the liquid preparations to remove fine

particles, imparting a greater clarity to solutions. Filtration

often presents problems, but with the help now available

from major filter manufacturers, most problems can be

readily solved. The formulators are urged to consult these

commercial suppliers.



There are four basic sensations: salty, bitter, sweet, and sour.

A combination of efforts is required to mask these tastes. For

example, menthol and chloroform act as desensitizing agents;

a large number of natural and artificial flavors and their combinations are available to mask the bitterness most often

found in organic compounds. Most formulators refer the

selection of compatible flavors to companies manufacturing

these flavors, as they may allow use of their drug master file

© 2004 by CRC Press LLC

Drugs are more unstable in solution or liquid dispersion

than they are in solid state because the molecular interactions are more plausible in liquid surroundings.


Physically stable liquid products are supposed to retain

their color, viscosity, clarity, taste, and odor throughout

the shelf life; however, the limits of the specifications for

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