PHARMACEUTICAL
MANUFACTURING
HANDBOOK
Regulations and
Quality
SHAYNE COX GAD, PH.D., D.A.B.T.
Gad Consulting Services
Cary, North Carolina
A JOHN WILEY & SONS, INC., PUBLICATION

PHARMACEUTICAL
MANUFACTURING
HANDBOOK
Regulations and
Quality

PHARMACEUTICAL
MANUFACTURING
HANDBOOK
Regulations and
Quality
SHAYNE COX GAD, PH.D., D.A.B.T.
Gad Consulting Services
Cary, North Carolina
A JOHN WILEY & SONS, INC., PUBLICATION
Copyright © 2008 by John Wiley & Sons, Inc. All rights reserved
Published by John Wiley & Sons, Inc., Hoboken, New Jersey
Published simultaneously in Canada
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10 9 8 7 6 5 4 3 2 1
CONTRIBUTORS
v
Emmanuel O. Akala, Department of Pharmaceutical Sciences, School of Pharmacy,
Howard University, Washington, DC, Effect of Packaging on Stability of Drugs
and Drug Products
Giuseppe Alibrandi, Universit à di Messina, Messina, Italy, Alternative Accelerated
Methods for Studying Drug Stability: Variable - Parameter Kinetics
Edward R. Arling, Amgen, Inc., Thousand Oaks, California, Creating and Managing

a Quality Management System
Christina Bartmann, Medical University of Graz, Graz, Austria, GMP - Compliant
Propagation of Human Multipotent Mesenchymal Stromal Cells
James M. Barquest, Ground Zero Pharmaceuticals, Inc., Irvine, California, Role of
Quality Systems and Audits in Pharmaceutical Manufacturing Environment
Denise Bohrer, Chemistry Department, Universidade Federal de Santa Maria,
Santa Maria, Brazil, Origin of Contamination
Chung Chow Chan, Azopharma Contract Pharmaceutical Services, Miramar,
Florida, Analytical Method Validation: Principles and Practices
Robert P. Cogdill, Duquense University Center for Pharmaceutical Technology,
Pittsburgh, Pennsylvania, Case for Process Analytical Technology: Regulatory and
Industrial Perspectives
Marc De Loose, Institute for Agricultural and Fisheries Research (ILVO), Scientifi c
Institute for the Flemish Community, Merelbeke, Belgium, Analytical Method
Validation and Quality Assurance
Katherine V. Domenick, Training and Communications Group, Inc., Berwyn,
Pennsylvania, Personnel Training in Pharmaceutical Manufacturing
vi CONTRIBUTORS
Michelle E. Dowling, Amgen, Inc., Thousand Oaks, California, Creating and Man-
aging a Quality Management System
L. Antonio Est é vez, University of Puerto Rico, Mayag ü ez, Puerto Rico, Drug
Stability
D.C. Ferreira, Faculty of Pharmacy, University of Porto, Porto, Portugal, Pharma-
ceutical Manufacturing Validation Principles
Alvin Fox, University of South Carolina, Columbia, South Carolina, Quantita-
tion of Markers for Gram - Negative and Gram - Positive Endotoxins in Work
Environment and as Contaminants in Pharmaceutical Products Using Gas
Chromatography – Tandem Mass Spectrometry
Paul A. Frankel, Amgen, Inc., Thousand Oaks, California, Creating and Managing
a Quality Management System

David A. Gallup, Training and Communications Group, Inc., Berwyn, Pennsylvania,
Personnel Training in Pharmaceutical Manufacturing
Srinivas Ganta, University of Auckland, Auckland, New Zealand, Scale - Up and
Postapproval Changes (SUPAC) Regulations
Sanjay Garg, University of Auckland, Auckland, New Zealand, Scale - Up and Post-
approval Changes (SUPAC) Regulations
Marge Gillis, Training and Communications Group, Inc., Berwyn, Pennsylvania,
Personnel Training in Pharmaceutical Manufacturing
James R. Harris, James Harris Associates, Inc., Durham, North Carolina, Good
Manufacturing Practices (GMP) and Related FDA Guidelines
Ashley John, New Jersey Institute of Technology, Newark, New Jersey, Analytical
and Computational Methods and Examples for Designing and Controlling Total
Quality Management Pharmaceutical Manufacturing Systems
Herman Lam, Wild Crane Horizon, Inc., Scarborough, Ontario, Canada, Validation
of Laboratory Instruments
Marko N ä rhi, Helsinki University of Technology, Helsinki, Finland, National GMP
Regulations and Codes and International GMP Guides and Guidelines: Corre-
spondences and Differences
Kenneth J. Nolan, Nolan & Auerbach, Fort Lauderdale, Florida, Enforcement of
Good Manufacturing Practices
Katrina Nordstr ö m, Helsinki University of Technology, Helsinki, Finland, National
GMP Regulations and Codes and International GMP Guides and Guidelines:
Correspondences and Differences
Nazario D. Ramirez - Beltran, University of Puerto Rico, Mayag ü ez, Puerto Rico,
Drug Stability
Gregory N. Ranky, Public Research University of New Jersey, Newark, New Jersey,
Analytical and Computational Methods and Examples for Designing and Control-
ling Total Quality Management Pharmaceutical Manufacturing Systems
CONTRIBUTORS vii
Paul G. Ranky, New Jersey Institute of Technology, Newark, New Jersey, Analytical

and Computational Methods and Examples for Designing and Controlling Total
Quality Management Pharmaceutical Manufacturing Systems
Richard G. Ranky, New Jersey Institute of Technology, Newark, New Jersey, Ana-
lytical and Computational Methods and Examples for Designing and Controlling
Total Quality Management Pharmaceutical Manufacturing Systems
Andreas Reinisch, Medical University of Graz, Graz, Austria, GMP - Compliant
Propagation of Human Multipotent Mesenchymal Stromal Cells
Harry Rodriguez, Cordis LLC, a Johnson & Johnson Company, San Juan, Puerto
Rico, Drug Stability
Yves Roggo, F. Hoffmann - La Roche, Ltd., Basel, Switzerland, Process Analytical
Technology; Chemical Imaging and Chemometrics: Useful Tools for Process Ana-
lytical Technology
Eva Rohde, Medical University of Graz, Graz, Austria, GMP - Compliant Propaga-
tion of Human Multipotent Mesenchymal Stromal Cells
B. Saramento, Faculty of Pharmacy, University of Porto, Porto, Portugal, Pharma-
ceutical Manufacturing Validation Principles
Katharina Schallmoser, Medical University of Graz, Graz, Austria, GMP -
Compliant Propagation of Human Multipotent Mesenchymal Stromal Cells
Puneet Sharma, University of Auckland, Auckland, New Zealand, Scale - Up and
Postapproval Changes (SUPAC) Regulations
Evan B. Siegel, Ground Zero Pharmaceuticals, Inc., Irvine, California, Role of
Quality Systems and Audits in Pharmaceutical Manufacturing Environment
E.B. Souto, Free University of Berlin, Berlin, Germany; Faculty of Pharmacy,
University of Porto, Porto, Portugal, Pharmaceutical Manufacturing Validation
Principles
Dirk Strunk, Medical University of Graz, Graz, Austria, GMP - Compliant Propaga-
tion of Human Multipotent Mesenchymal Stromal Cells
Michel Ulmschneider, F. Hoffman - La Roche, Ltd., Basel, Switzerland, Process Ana-
lytical Technology; Chemical Imaging and Chemometrics: Useful Tools for Process
Analytical Technology

Isabel Taverniers, Institute for Agricultural and Fisheries Research (ILVO), Scien-
tifi c Institute for the Flemish Community, Merelbeke, Belgium, Analytical Method
Validation and Quality Assurance
Erik Van Bockstaele, Institute for Agricultural and Fisheries Research (ILVO),
Scientifi c Institute for the Flemish Community, Merelbeke, Belgium, Analytical
Method Validation and Quality Assurance
T. Vasconcelos, Laboratory of Pharmaceutical Development, BIAL, Mamede do
Coronado, Portugal; Faculty of Pharmacy, University of Porto, Porto, Portugal,
Pharmaceutical Manufacturing Validation Principles
viii CONTRIBUTORS
Ranga Velagaleti, BASF Corporation, Florham Park, New Jersey, Microbiology of
Nonsterile Pharmaceutical Manufacturing; Stability and Shelf Life of Pharmaceu-
tical Products
Andrew A. Webster, McWhorter School of Pharmacy, Birmingham, Alabama, Phar-
maceutical Product Stability
Jyh - hone Wang, University of Rhode Island, Kingston, Rhode Island, Quality
Process Improvement
ix
CONTENTS
PREFACE xiii
SECTION 1 GOOD MANUFACTURING PRACTICES (GMP) AND
OTHER FDA GUIDELINES 1
1.1 Good Manufacturing Practices (GMPs) and Related FDA
Guidelines 3
James R. Harris
1.2 Enforcement of Current Good Manufacturing Practices 45
Kenneth J. Nolan
1.3 Scale-Up and Postapproval Changes (SUPAC) Regulations 67
Puneet Sharma, Srinivas Ganta, and Sanjay Garg
1.4 GMP-Compliant Propagation of Human Multipotent Mesenchymal

Stromal Cells 97
Eva Rohde, Katharina Schallmoser, Christina Bartmann, Andreas Reinisch,
and Dirk Strunk
SECTION 2 INTERNATIONAL REGULATIONS OF GOOD
MANUFACTURING PRACTICES 117
2.1 National GMP Regulations and Codes and International GMP
Guides and Guildelines: Correspondences and Differences 119
Marko Närhi and Katrina Nordström
x CONTENTS
SECTION 3 QUALITY 163
3.1 Analytical and Computational Methods and Examples for Designing
and Controlling Total Quality Management Pharmaceutical
Manufacturing Systems 165
Paul G. Ranky, Gregory N. Ranky, Richard G. Ranky, and Ashley John
3.2 Role of Quality Systems and Audits in Phatmaceutical
Manufacturing Environment 201
Evan B. Siegel and James M. Barquest
3.3 Creating and Managing a Quality Management System 239
Edward R. Arling, Michelle E. Dowling, and Paul A. Frankel
3.4 Quality Process Improvement 287
Jyh-hone Wang
SECTION 4 PROCESS ANALYTICAL TECHNOLOGY (PAT) 311
4.1 Case for Process Analytical Technology: Regulatory and Industrial
Perspectives 313
Robert P. Cogdill
4.2 Process Analytical Technology 353
Michel Ulmschneider and Yves Roggo
4.3 Chemical Imaging and Chemometrics: Useful Tools for Process
Analytical Technology 411
Yves Roggo and Michel Ulmschneider

SECTION 5 PERSONNEL 433
5.1 Personnel Training in Pharmaceutical Manufacturing 435
David A. Gallup, Katherine V. Domenick, and Marge Gillis
SECTION 6 CONTAMINATION AND CONTAMINATION
CONTROL 455
6.1 Origin of Contamination 457
Denise Bohrer
6.2 Quantitation of Markers for Gram-Negative and Gram-Positive
Endotoxins in Work Environment and as Contaminants in
Pharmaceutical Products Using Gas Chromatography–Tandem
Mass Spectrometry 533
Alvin Fox
6.3 Microbiology of Nonsterile Pharmaceutical Manufacturing 543
Ranga Velagaleti
CONTENTS xi
SECTION 7 DRUG STABILITY 557
7.1 Stability and Shelf Life of Pharmaceutical Products 559
Ranga Velagaleti
7.2 Drug Stability 583
Nazario D. Ramirez-Beltran, Harry Rodriguez, and L. Antonio Estévez
7.3 Effect of Packaging on Stability of Drugs and Drug Products 641
Emmanuel O. Akala
7.4 Pharmaceutical Product Stability 687
Andrew A. Webster
7.5 Alternative Accelerated Methods for Studying Drug Stability:
Variable-Parameter Kinetics 701
Giuseppe Alibrandi
SECTION 8 VALIDATION 725
8.1 Analytical Method Validation: Principles and Practices 727
Chung Chow Chan

8.2 Analytical Method Validation and Quality Assurance 743
Isabel Taverniers, Erik Van Bockstaele, and Marc De Loose
8.3 Validation of Laboratory Instruments 791
Herman Lam
8.4 Pharmaceutical Manufacturing Validation Principles 811
E. B. Souto T. Vasconcelos D. C. Ferreira, and B. Sarmento
INDEX 839

xiii
PREFACE
This Handbook of Manufacturing: Regulations and Quality focuses on all regulatory
aspects and requirements that govern how drugs are produced for evaluation (and,
later, sale to and use in) humans. The coverage ranges from what the issues are at
the early stages (when the amounts are small and the materials of limited sophistica-
tion) up to until the issue is reproducibly and continuously making large volumes
of a highly sophisticated manufactured product. These 25 chapters cover the full
range from preformulation of a product (the early exploratory work that allows us
to understand how to formulate and deliver the drug) to identifi cation of sources
of contamination and assessment of stability.
The Handbook of Manufacturing: Regulations and Quality seeks to cover the
entire range of available approaches to satisfying the wide range of regulatory
requirements for making a highly defi ned product that constitutes a successful new
drug and how to do so in as effective and as effi cient a manner as possible.
Thanks to the persistent efforts of Michael Leventhal, these 25 chapters, which
are written by leading practitioners in each of these areas, provide coverage of the
primary approaches to the fundamental regulatory challenges that must be over-
come to manufacture successfully a deliverable and stable new drug.

GOOD MANUFACTURING PRACTICES
( GMP ) AND OTHER FDA GUIDELINES

SECTION 1

3
1.1
Pharmaceutical Manufacturing Handbook: Regulations and Quality, edited by Shayne Cox Gad
Copyright © 2008 John Wiley & Sons, Inc.
GOOD MANUFACTURING
PRACTICES ( GMP ) AND RELATED
FDA GUIDELINES
James R. Harris
James Harris Associates, Inc., Durham, North Carolina
Contents
1.1.1 FDA Regulations: Real and Imagined
1.1.2 21 CFR 210 and 211: Current Good Manufacturing Practice for Finished
Pharmaceuticals
1.1.3 Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Good
Manufacturing Practice Regulations
1.1.3.1 CGMPS and the Concepts of Modern Quality Systems
1.1.3.2 Quality Systems Model
1.1.4 Guidance for Industry: PAT — Framework for Innovative Pharmaceutical Develop-
ment, Manufacturing, and Quality Assurance
1.1.4.1 PAT Framework
1.1.5 Guidance for Industry: Part 11. Electronic Records; Electronic Signatures — Scope and
Application
1.1.6 Guidance for Industry and FDA: Current Good Manufacturing Practice for Combina-
tion Products
1.1.7 Guidance for Industry: Powder Blends and Finished Dosage Units — Stratifi ed In -
Process Dosage Unit Sampling and Assessment
1.1.7.1 Validation of Batch Powder Mix Homogeneity
1.1.7.2 Verifi cation of Manufacturing Criteria

1.1.8 Guidance for Industry: Immediate - Release Solid Oral Dosage Forms Scale - Up and
Postapproval Changes (SUPAC) — Chemistry, Manufacturing and Controls, In Vitro
Dissolution Testing, and In Vivo Bioequivalence Documentation
1.1.9 Other GMP - Related Guidance Documents
4 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES
1.1.1 FDA REGULATIONS: REAL AND IMAGINED
A regulation is a law. In the United States, all federal laws have been arranged or
codifi ed in a manner that makes it easier to fi nd a specifi c law. The Code of Federal
Regulations (CFR) is a compilation of all federal laws published in the Federal
Register by the executive departments and agencies of the federal government. This
code is divided into 50 titles which represent broad areas of federal regulation. Each
title is further divided into chapters. The chapters are then subdivided into parts
covering specifi c regulatory areas. Changes and additions are fi rst published in the
Federal Register . Both the coded law and the Federal Register must be used to deter-
mine the latest version of any rule. All food - and drug - related laws are contained
in Title 21 of the CFR. Each title of the CFR is updated annually. Title 21 is updated
as of April 1 of each year.
Because virtually all of the drug regulations are written to state what should be
done but do not tell how to do it, the Food and Drug Administration (FDA) also
publishes guidance documents. These documents are intended to provide precisely
what the name implies — guidance. In this context, guidance documents are not law
and do not bind the FDA or the public . Manufacturers are not required to use the
techniques or approaches appearing in the guidance document. In fact, FDA rep-
resentatives have repeatedly stated that the regulations were not written to suggest
how something should be done in order to encourage innovation. While following
the recommendations contained in the guidance documents will probably assure
acceptance (agency philosophy and interpretation may have changed since the guid-
ance document was published), other approaches are encouraged. No matter how
they choose to proceed, manufacturers should be prepared to show that their
methods achieve the desired results.

A method used by the FDA to “ fl oat ” new ideas is to discuss them at industry
gatherings such as FDA - sponsored seminars or meetings of industry groups such as
the Pharmaceutical Manufacturers Association (PMA), the Parenteral Drug Asso-
ciation (PDA), and the International Society of Pharmaceutical Engineering (ISPE).
Again, it must be remembered that while these comments refl ect current FDA
thinking, they are simply thoughts and recommendations. They are not law.
Several industry groups also publish comments, guidelines, and so on, that put
forth current thinking of the group writing the document. These publications are
interesting and often bring out valuable information. However, it is important to
remember that these publications are not regulations or even offi cial guidance docu-
ments. If a fi rm chooses to follow the recommendations of such documents, they are
probably following good advice. However, since the advice comes from a nonoffi cial
source, fi rms should still be prepared to defend their actions with good scientifi c
reasoning.
1.1.2 21 CFR 210 AND 211: CURRENT GOOD MANUFACTURING
PRACTICE FOR FINISHED PHARMACEUTICALS
Parts 210 and 211 of CFR Title 21 are the laws defi ning good manufacturing prac-
tices for fi nished pharmaceutical products. All manufacturers must follow these
regulations in order to market their products in the United States. When a fi rm fi les
an application to market a product in the United States through a New Drug Appli-
cation (NDA), abbreviated NDA, (ANDA), Biological License Application (BLA),
CURRENT GOOD MANUFACTURING PRACTICE 5
or other product application, one of the last steps in approving the application is a
preapproval inspection of the manufacturing facility. A major purpose of this inspec-
tion is to assure adherence to the GMP regulations. Preapproval inspections are a
part of every application approval. Thus, if a fi rm has 10 applications pending, it
should expect 10 inspections. The fact that the manufacturing facility has already
been inspected will not alter the need for another inspection.
The FDA also has the right to visit and inspect any manufacturing facility that
produces a product or products sold in the United States. Such inspections are unan-

nounced. A manufacturer must admit an inspector when he or she appears at that
facility and must do so without undue delay.
GMP requirements for manufacturers of pharmaceutical dosage forms are dis-
cussed below. This information should not be considered to be an exact statement
of the law. We have attempted to show intent and, occasionally, add some comments
that will clarify how that particular regulation is interpreted. For precise wording of
a regulation, refer to the CFR and then check the Federal Register to determine if
there have been any changes since the last update.
General Provisions
1. This section pertains to the manufacture of drug products for humans or
animals.
2. These requirements will not be enforced for over - the - counter (OTC) drug prod-
ucts if the products and all their ingredients are ordinarily marketed and consid-
ered as human foods and which products may also fall within the legal defi nition
of drugs by virtue of their intended use.
Organization and Personnel
1. Responsibilities of quality control unit
(a) A quality control unit must be a part of the facility organization.
(b) This unit must be given responsibility and authority to approve or reject all
components, drug product containers, closures, process materials, packaging
material, labeling, and drug products, and the authority to review production
records.
(c) Adequate laboratory facilities for testing and approval or rejection of the
above listed materials must be available.
(d) The quality control unit is responsible for approving or rejecting all proce-
dures or specifi cations that impact on the identity, strength, quality, and purity
of the drug product.
(e) Responsibilities and procedures applicable to the quality control unit must
be written and these procedures must be followed.
2. Personnel qualifi cations

(a) Every person involved in the manufacture, processing, packing, or holding of
a drug product must have education, training, and experience that enable
that individual to perform their duties. Employees must be trained in the
particular operations that they perform and in Current GMPs (CGMPs). The
GMP training must be conducted by qualifi ed individuals and with suffi cient
frequency to assure that workers remain familiar with the requirements
applicable to them.
6 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES
(b) Persons responsible for supervision must have the education, training, and
experience to perform their assigned functions in such a manner as to assure
that the drug product has the safety, identity, strength, quality, and potency
that it is represented to possess.
(c) There must be an adequate number of qualifi ed personnel to perform the
needed tasks.
3. Personnel responsibilities
(a) Personnel shall wear clean clothing appropriate for the duties they perform.
Protective apparel must be worn as necessary.
(b) Personnel shall practice good sanitation and health habits.
(c) Only personnel authorized by supervisory personnel shall enter those areas
designated as limited - access areas.
(d) Any worker considered to have an apparent illness or open lesions that may
adversely affect safety or quality of drug products shall be excluded from
direct contact with product, components, or containers.
4. Consultants that advise on the manufacture, processing, packing, or holding of
drug products must have suffi cient education, training, and experience to advise
on the subject for which they are retained. The manufacturer must maintain
records of name, address, and qualifi cations of any consultants and the type of
service they provide.
Buildings and Facilities
1. Design and construction features

(a) Buildings should be of suitable size, construction location to facilitate clean-
ing, maintenance, and proper operations.
(b) Space should be adequate for the orderly placement of equipment and mate-
rials to prevent mix - ups between different components, drug product con-
tainers and closures, labeling, in - process materials, or drug products and to
prevent contamination.
(c) The movement of components and product through the building must be
designed to prevent contamination.
(d) Operations should be performed within specifi cally defi ned areas having
adequate control systems to prevent contamination or mix - ups during each
of the following procedures:
(i) Receipt, identifi cation, storage, and withholding from use of compo-
nents, drug product containers, closures, and labeling, pending the
appropriate sampling, testing, and release for manufacturing or
packaging.
(ii) Holding rejected materials listed in (a) above.
(iii) Storage of released components, drug product containers, closures, and
labeling.
(iv) Storage of in - process materials.
(v) Manufacturing and processing operations.
(vi) Packaging and labeling operations.
(vii) Quarantine storage before release of drug products.
(viii) Storage of drug products after release.
(ix) Control and laboratory operations.
CURRENT GOOD MANUFACTURING PRACTICE 7
(x) Aseptic processing, which includes:
(1) Floors, walls, and ceilings of smooth, hard surfaces that are easily
cleanable.
(2) Temperature and humidity controls.
(3) An air supply fi ltered through High - Effi ciency Particulate Air

(HEPA) fi lters under positive pressure regardless of whether fl ow
is laminar or nonlaminar.
(4) A system for monitoring environmental conditions.
(5) A system for cleaning and disinfecting the room and equipment to
produce aseptic conditions.
(6) A system for maintaining any equipment used to control the aseptic
conditions.
(e) Operations relating to the manufacture, processing, and packing of penicillin
must be performed in facilities separate from those used for other drug
products for humans. Note : For all purposes of these GMP regulations, the
FDA considers cephalosporins to be penicillin.
2. Adequate lighting should be provided in all areas.
3. Heating, ventilation, and air conditioning (HVAC)
(a) Adequate ventilation is required in all areas.
(b) Equipment for adequate control over air pressure, microorganisms, dust,
humidity, and temperature must be provided when appropriate for the manu-
facture, processing, packing, or holding of a drug product.
(c) When appropriate, air supplied to production areas should be fi ltered to
avoid any possibility of contamination or cross - contamination.
(d) Air - handling systems for the manufacture, processing, and packing of penicil-
lin shall be completely separate from those for other drug products for
humans.
4. Plumbing
(a) Potable water should be supplied in a continuous positive - pressure system
free from defects that could contribute to contamination of any drug
product.
(b) Potable water must meet the standards prescribed in the Environmental
Protection Agency (EPA) Primary Drinking Water Regulations defi ned in
40 CFR Part 141.
(c) Drainage must be of adequate size. Where connected directly to a sewer, an

air break or other suitable mechanical device must be provided to prevent
back - siphonage.
5. Sewage, trash, and other refuse in and from the building and immediate premises
must be disposed of in a safe and sanitary manner.
6. Adequate washing facilities should be provided. This is to include hot and cold
water, soap or detergent, air driers or single - service towels, and clean toilet facili-
ties easily accessible to all work areas.
7. Sanitation
(a) Any building used for manufacture, processing, packing, or holding of a drug
product should be maintained in a clean and sanitary condition. Such buildings
should be free of infestation by rodents, birds, insects, and other vermin.
(b) Trash and organic waste matter should be held and disposed of in a timely
and sanitary manner.
8 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES
(c) Written procedures assigning responsibility for sanitation and describing in
suffi cient detail the cleaning schedules, methods, equipment, and materials
to be used in cleaning the buildings and facilities are required. Such proce-
dures must be followed.
(d) Written procedures for use of suitable rodenticides, insecticides, fungicides,
fumigating agents, and cleaning and sanitizing agents are required and must
be followed. These written procedures should be designed to prevent the
contamination of equipment, components, product containers, closures, pack-
aging, labeling materials, or drug products. Agent may not be used unless
registered and used in accordance with the Federal Insecticide, Fungicide,
and Rodenticide Act (7 U.S.C. 135).
(e) All sanitation procedures apply equally to contractors or temporary employ-
ees as to regular employees.
8. All buildings used for GMP - related purposes must be maintained in a good state
of repair.
Equipment

1. Equipment should be of appropriate design, adequate size, and suitably located
to facilitate operations for its intended use and for cleaning and maintenance.
2. Equipment construction
(a) Equipment should be constructed so that surfaces that contact components,
in - process materials, or drug products should not be reactive, additive, or
absorptive so as to alter the safety, identity, strength, quality, or purity of the
drug product beyond offi cial or other established requirements.
(b) Any substance required for operation such as lubricants or coolants shall not
come into contact with drug products, containers, and so on, so as to alter
the safety, identity, strength, quality, or purity of the drug product beyond
established requirements.
3. Equipment cleaning and maintenance
(a) Equipment and utensils should be cleaned, maintained, and sanitized at
appropriate intervals to prevent malfunctions or contamination that would
alter the drug product beyond the offi cial requirements.
(b) Written procedures must be established and followed for cleaning and
maintenance of equipment and utensils used in the processing of a drug
product. These procedures must include but are not limited to the
following:
(i) Assignment of responsibility for cleaning and maintaining equipment.
(ii) Maintenance and cleaning schedules, including sanitizing schedules if
appropriate.
(iii) A suffi ciently detailed description of the methods, equipment, and
materials used in cleaning and maintenance operations and the methods
of disassembling and reassembling equipment as a part of cleaning and
maintenance.
(iv) Removal or obliteration of previous batch identifi cation.
(v) Protection of clean equipment from contamination prior to use.
(vi) Inspection of equipment for cleanliness immediately before use.
CURRENT GOOD MANUFACTURING PRACTICE 9

(vii) Records should be kept of maintenance, cleaning, sanitizing, and inspec-
tion of all processing equipment.
4. Automatic, mechanical, and electronic equipment
(a) All such equipment, including computers or related systems that will perform
a function to be used in any GMP - related activity, must be routinely cali-
brated, inspected, or checked according to a written program designed to
assure proper performance. Written records must be maintained for all such
activities.
(b) Appropriate controls should be exercised to assure that changes in master
production and control records or other similar records are made only by
authorized personnel. Input to and output from such systems should be
checked for accuracy.
A backup fi le of data entered into a computer - related system must be
maintained except where certain data such as calculations performed in con-
nection with laboratory analysis are eliminated by computerization or other
automated processes. In this situation, a written record of the program should
be maintained along with validation data.
5. Filters for liquid fi ltration used as a part of the manufacture, processing, or
packing of injectable drug products intended for human use must not release
fi bers into such products. Fiber - releasing fi lters may not be used unless it is not
possible to manufacture the product without the use of such a fi lter. In this situ-
ation, an additional non - fi ber - releasing fi lter of 0.22 μ m maximum must be used
after the fi ber - releasing fi ltration. Use of an asbestos - containing fi lter is permis-
sible only upon submission of proof to the appropriate FDA bureau that use of
a non - fi ber - releasing fi lter will compromise the safety or effectiveness of the drug
product.
Control of Components and Drug Product Containers and Closures
1. General requirements
(a) There must be written procedures describing in suffi cient detail the receipt,
identifi cation, storage, handling, sampling, testing, and approval or rejection

of product components, containers, and closures. Of course, all such proce-
dures must be followed. It is quite common and even more embarrassing to
be cited for not following your own written procedures. Note: For the rest of
this discussion, the term components will mean product ingredients, contain-
ers, closures, and so on.
(b) All components listed above must be handled and stored in a manner that
will prevent contamination.
(c) Bagged or boxed components should be stored off the fl oor. Spacing should
allow cleaning and inspection.
(d) Every container of components must be identifi ed with a distinctive code or
lot number for each receival of that product. Even if the next receival is the
same vendor lot number, it must be a new identifying number by the phar-
maceutical manufacturer. Each lot must be appropriately identifi ed as to its
status (quarantined, approved, or rejected).