FDA Questions and Answers

GMP & Validation.......................................................................................................................1

Water Systems.............................................................................................................................7
CIP Systems................................................................................................................................9

GMP & Validation

Does FDA approve materials of construction for equipment? For example, are there any
specific CGMP requirements regarding ferrite content and other properties of 316L
stainless steel used in storage tanks for pharmaceutical water systems?

Reference:21 CFR Sections 211.63, Equipment design, size, and location, 211.72, Filters,
211.65, Equipment construction, 211.67, Equipment cleaning and maintenance, and 211.48,
Plumbing; Guide To Inspections Of High Purity Water Systems, July, 1993.

FDA does not approve or prohibit specific equipment or materials (with rare exceptions such
as the requirements relating to asbestos filters found at 21 CFR 211.72). A storage tank or
other piece of equipment is subject to the general CGMP requirements addressing equipment
suitability. For example, section 211.65 requires surfaces that contact components, in-process
materials, or drug products not be reactive, additive, or absorptive so as to adversely affect
product quality. Section 211.63 requires that equipment be of appropriate design to facilitate
operations for its intended use and for cleaning and maintenance. Section 211.67 requires
firms to clean, maintain, and sanitize equipment at appropriate intervals to prevent
malfunctions or contamination that would adversely affect product quality.

To illustrate, it's important that interior surfaces of a sanitary storage tank are capable of being
cleaned, sanitized, and (if needed) sterilized. For such sanitary equipment, design provisions
to prevent backsiphonage (see Section 211.48) and stagnation are among the attributes that
prevent microbial contamination of a drug product. Likewise, smooth interior surfaces (e.g.,
welds) help prevent collection of microbial contamination and formation of a biofilm. (See
the above inspection guide for more information on biofilms.)

So choosing materials or components for any equipment involves evaluating whether there is
any potential for an adverse impact on drug product quality. In this respect, various
compatibility considerations (e.g., leachables, interaction with formulations/sanitizers, ability
of material to withstand sterilization) can often take on the most CGMP significance.

Ultimately, provided that such CGMP requirements are met, firms are afforded the flexibility
to select the material and grade which best satisfies the needs of their particular application.
Given this information, it should be no surprise that the CGMP regulations do not include
specifics on what ferrite content is appropriate in stainless steel. However, a number of
references may provide a useful starting point when researching issues such as sanitary design
standards, surface grit/smoothness, pits, folds, crevices, and steel composition (including
ferrite content). The milk industry has publications (e.g., "3-A Accepted Practices for
Permanently Installed Sanitary Product Pipelines and Cleaning Systems") written jointly with
the U.S. Public Health Service regarding sanitary design. ANSI (American National Standards

Alfa Laval Pharma Seminar, October 2005 1

Institute) also publishes documents addressing design of seamless and sanitary piping. Such
literature should be available through a search on the American Iron and Steel Institute (1000
16th Street, N.W., Washington, D.C. 20036) website at www.steel.org. A search on words
such as "seamless" and "weld" at www.nssn.org will yield further relevant references.

Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail:

friedmanr@cder.fda.gov

Is there a list of approved drug manufacturing equipment?

No. The CGMP regulations neither approve nor prohibit specific equipment for use in
manufacturing of pharmaceutical products (with the exception of asbestos and fibre-releasing
filters, see 211.72). We do not maintain a list of approved equipment. Firms are afforded the
flexibility to select equipment that best satisfies their particular needs and that is capable of
meeting the relevant CGMP requirements. Each firm is responsible for selecting all
equipment used in their manufacturing process to produce quality product in accordance with
CGMP. They are also responsible for selecting the appropriate intended use for the
equipment's operation, and are free to modify standard equipment designs to best suit their
process and that are compatible with the product under process.
The CGMPs require that equipment be of appropriate design to facilitate operations for its
intended use and for cleaning and maintenance (see 211.63 and 211.67) and, that any
equipment surface in contact with components, in-process materials, or drug products not be
reactive, additive, or absorptive so as to "alter the safety, identity, strength, quality, or purity
of the drug product beyond the official or other established requirements" (see 211.65).
References:

 21 CFR 211.63: Equipment design, size, and location

 21 CFR 211.65: Equipment construction

 21 CFR 211.67: Equipment cleaning and maintenance

 21 CFR 211.68: Automatic, mechanical, and electronic equipment

 21 CFR 211.72: Filters

Contact for further information: Anthony Charity, CDER

charitya@cder.fda.gov

Validation and equipment qualification; when "identical" really isn't.

Reference: 21 CFR 211.100, Written procedures, deviations; Guideline On General Principles

of Process Validation, May, 1987

As explained in the 1987 validation guideline, the general requirement for process validation
is contained in section 211.100 of the CGMP regulations which states that "[T]here shall be
written procedures for production and process control designed to assure that the drug

Alfa Laval Pharma Seminar, October 2005 2

products have the identity, strength, quality, and purity they purport or are represented to
possess."

The validation guideline addresses several general principles of equipment suitability. For
example, installation qualification is described as establishing confidence that process
equipment and ancillary systems are capable of consistently operating within established
limits and tolerances. Installation qualification includes examination of equipment design,
determination of calibration, maintenance, and adjustment requirements, and identifying
critical equipment features that could affect the process and product. Another principle is that
equipment is evaluated and tested to verify that it is capable of operating satisfactorily within
the required process operating limits and that actual production conditions, including "worst
case" situations, are simulated. The guideline cautions that "[I]n assessing the suitability of a
given piece of equipment, it is usually insufficient to rely solely upon the representations of
the equipment supplier…"

The guideline further states that each specific process should be appropriately qualified and
validated, noting the inherent danger in relying on perceived similarities between products,
processes, and equipment.

The following case illustrates the importance of performing adequate equipment qualification
on each piece of processing equipment, and the problems that may result when firms fail to
verify equipment supplier representations.

A pharmaceutical firm used two blenders to produce a tablet. Both blenders were from the
same equipment manufacturer, had the same model number and same design. Although one
blender was older than the other, the supplier told the drug manufacturer that the units were
"identical." The drug manufacturer took the claim at face value and did not include the older
blender as part of its process validation.

The drug company marketed about 100 lots of tablets made using the old blender. In testing
retain samples, the company found that some lots failed the content uniformity specification.

The firm's investigation traced the out of specification lots to one of the two "identical"
blenders, namely the old one. The pharmaceutical firm's own investigation found the older
blender to have a slightly smaller capacity and different RPM (revolutions per minute)
operational characteristics when run at the same settings as the newer blender.

Subsequently, the firm recalled its total production of the product it made using the older
blender. This extensive recall involved multiple strengths of product totaling approximately
one half million bottles from U.S. and foreign consignees. The firm plans to qualify the old
blender using production size lots.

In light of this case study, during your audits of a firm's process validation, it would be
appropriate to determine if the firm's validation protocol includes equipment qualification for
all units of significant equipment, even where multiple units are supposedly "identical."
Moreover, as explained in the validation guideline, the validation should reflect production
size lots.

Contact for further information: Michael J.Verdi, HFD-301, 301-594-2456; e-mail:

verdim@cder.fda.gov

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Has FDA established a required number of runs to be performed during Operational
Qualification (OQ) testing? If a firm qualifies one type and model of equipment, can it be
used in a different process without additional qualification?

Reference: 21 CFR 211.100, Written procedures; deviations; May 1987, Guideline on General
Principles of Process Validation

Installation Qualification (IQ), Operational Qualification (OQ), and Performance

Qualification (PQ), along with other similar terms, are commonly used in the pharmaceutical
industry to discuss the generally accepted concept that a firm should qualify equipment and
systems as part of validating a manufacturing process. The FDA Guideline on General
Principles of Process Validation does not use the term Operational Qualification. It defines
Installation Qualification as establishing confidence that process equipment and ancillary
systems are capable of consistently operating within established limits and tolerances. This
includes IQ and OQ. The FDA Guideline also defines Process Performance Qualification as
establishing confidence that the process is effective and reproducible.

The guideline states that "it is important that equipment qualification simulate actual
production conditions, including those which are 'worst case' situations," and that "tests and
challenges should be repeated a sufficient number of times to assure reliable and meaningful
results."

Regarding the first question, the often-cited "three consecutive batch" recommendation is
intended for process validation rather than for equipment qualification. FDA has not
recommended any specific number of "runs" for equipment qualification, but expects multiple
tests to simulate actual operating ranges and to establish consistency.

As to the second question, FDA expects Installation Qualification on each piece of equipment
to document that it is installed correctly and operates consistently according to established
limits and tolerances. Operational Qualification should also be performed for each different
use of the equipment or system to document the suitability for that use, but would not be
required for additional pieces of the same type/model of equipment when used in the same
process. Process Performance Qualification would also not be required for each piece of the
same type/model of equipment used in the same process, provided installation qualification
has been performed.

Contact for further info: John Dietrick, HFD-325, 301-594-0098; e-mail:

dietrickj@cder.fda.gov

Where are the requirements of current good manufacturing practice (CGMP) stated? How
are they applied?

References: See 21 CFR 210 and 211; 21 U.S.C. Federal Food, Drug, and Cosmetic Act, as
amended; 21 U.S.C. 331(k)

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The Food, Drug and Cosmetic Act establishes the requirement that all drugs must be made
under "current good manufacturing practice".

Specific CGMP requirements for human drugs are established in the regulations, "Current
Good Manufacturing Practices for Finished Pharmaceuticals" (21 CFR Parts 210 and 211).
These regulations state requirements because they are substantive ( i.e., they are binding
regulations).

What FDA can enforce as CGMP is derived from the general CGMP requirement of the Act,
as well as the CGMP regulations. However, if a given practice is not specified in the
regulations, FDA has the burden of proving that the practice is, by law, nonetheless CGMP.

During your inspections, be sure that your CGMP related inspectional observations state a
failure or an inadequacy against a requirement, i.e., against a provision of the CGMP
regulations or CGMP in general.

While the agency publishes a variety of guidance documents (guidance to industry, guides to
inspection, etc) containing important recommendations about how to meet individual
requirements of the CGMP regulations, the recommendations are neither binding nor the basis
for a CGMP requirement. They are not the only way a requirement may be met. If a firm
presents an alternative, it should be evaluated based on its merits.

Other bodies like the USP, trade associations, and individuals publish information on various
aspects of drug manufacturing. Such information should not be viewed as the basis for a
CGMP requirement by the sole virtue of having been published. No FDA guidance document
or external treatise should be referenced in an inspectional observation as the basis for a
CGMP requirement unless, by coincidence, the practice at issue is, in fact, required by the
regulations or law.

When establishing CGMP requirements, FDA uses the standard of whether a practice is
"feasible and valuable" in contributing to assurance of drug safety, quality and purity.
Although we consider what is actually done in the industry, before we view a practice as
CGMP it need not be predominant in the industry.

The CGMP regulations embody minimum requirements, standards below which products are
deemed adulterated.

Only those parts of the CGMP regulations which apply to operations in which a manufacturer
is engaged are requirements for that manufacturer.

The CGMP regulations apply to:

* both prescription and OTC drug products, including homeopathic drugs;

* manufacturing facilities of all sizes, large or small.

* the manufacture of drug products in the investigational phase of development when they are
produced for clinical trials.

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* the manufacture of drug products in foreign facilities where the products are distributed in
the United States, or otherwise introduced into interstate commerce.

While the requirements in the Act to observe CGMP apply to wholesales, retailers,
pharmacies and hospitals (by the application of Sec. 301(k)), the CGMP regulations don't
apply unless such organizations engage in manufacturing operations beyond the usual
dispensing or selling of drugs at retail.

The CGMP requirements of the Act apply to the manufacture of active pharmaceutical
ingredients (APIs) and other bulk drugs, but the CGMP regulations do not apply. However,
there are numerous instances where CGMP for APIs and other bulk drugs parallel the those in
the CGMP regulations. For this reason, we use the standards in the CGMP regulations as
guidance for inspecting facilities engaged in this type of manufacturing. We are also preparing
a specific CGMP guidance document for APIs.

The CGMP regulations do not apply to OTC products if those products and all their
ingredients are ordinarily marketed and consumed as human food ( e.g., some candy cough
drops).

Where a class of drugs is exempt from a given section of the regulations, the exemption is
stated in the section. For example, homeopathics, some allergenics, and some OTCs are
exempt from section 211.137 as stated in that section.

Contact for Further Info: Nicholas Buhay, HFD-325, 301-594-0098; e-

mail:buhay@cder.fda.gov

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 Water Systems

What is the significance of the Total Organic Carbon (TOC) test for compendial processing
waters (Purified Water, Water for Injection)?

Reference: 21 CFR 211.80 General requirements [Subpart E-Control of Components and

Drug Product Containers and Closures]; 211.84, Testing and approval or rejection of
components, drug product containers, and closures

Implicit in the term "Purified Water" is that it has some reasonable, objective level of purity.
TOC testing allows for evaluating impurities in water besides those which are inorganic
anions and cations. Carbon-based (organic) compounds are often more complex than
inorganic impurities. TOC allows for a quick, broad test for organic impurities. Numerous
compounds can be detected under the umbrella of TOC, but it is important to be aware that
this method is not capable of differentiating between specific organic compounds.

There is a long history of testing water for the presence of organic compounds. TOC's
predecessor, oxidizable substances, is widely considered a less accurate, outdated test. As of
May, 1998, TOC is the official organic impurities test for USP pharmaceutical processing
waters.

Contact for further information: Richard L. Friedman, HFD- 322, 301-594-0095; e-mail:
friedmanr@cder.fda.gov

What should firms use as microbial limits for purified water?

Reference: 21 CFR 211.113, Control of microbiological contamination; 211.84(c)(6), Testing

and approval or rejection of components, drug product containers, and closures.

In the CGMP context firms should set and justify their own microbial limits for purified water
(PW) based on at least two factors in production. First is the microbial specification of the
finished product or the equipment surfaces which contact the water. The microbial limit for
the water as a component should be more stringent than the limit set for the end product. For
example, where a finished product has a microbial limit of not more than 100 cfu/ml, the
corresponding limit for water as an ingredient in that product should be less than 100 cfu/ml.

The second factor is the validated water system's operational data. Properly controlled and
well designed PW systems should be capable of producing validated water quality in the
range of 30-50 cfu/ml. Such operational data would not justify establishing a less stringent
specification of "not more than 100 cfu/ml."

Contact for further information: Michael J. Verdi, HFD-322, 301-594-0095; e-mail:

verdim@cder.fda.gov

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When do the changes in USP water monographs chemical testing take effect?

Reference: USP XXIII/NF XVIII, Supplement 5.

In Supplement 5, the USP published changes in testing water covered by several monographs,
including Purified Water and Water for Injection, effective November 15, 1996. The revisions
include: 1) a new test for Total Organic Carbon (TOC) <643> which will ultimately replace
Oxidizable Substances (OS); and 2) a Water Conductivity <645> analysis, replacing several
wet chemistry tests. The test for pH remains. These changes in testing were made to take
advantage of modern analytical technology and for better cost effectiveness. The changes do
not tighten standards for pharmaceutical water.

The test for OS has not been deleted with the addition of the test for TOC. The intent of the
USP is to accommodate the interim use of OS while firms phase-in TOC. It is expected that
the deletion of the OS test from the USP will become official in May 1998. At present either
of these tests is acceptable to CDER and CBER. CDER and CBER expect compliance with
the Water Conductivity test.

On-line meters for testing water conductivity or TOC should be installed in a location in the
water system which reflects the quality of the process water. If worst-case placement is not
used, laboratories should continue performing these USP water monograph tests as part of a
routine sampling program which covers each point-of-use.

Contact for Further Information: (for CDER) Richard L. Friedman, HFD-322, 301-594-0095;
e-mail: friedmanr@cder.fda.gov; or, (for CBER) Walter Lange, Division of Establishment
Licensing, HFM-205, (301) 827-3031

Does FDA "prefer" polyvinylidene difluoride over stainless steel for construction of
recirculating loops in water for injection (WFI) systems?

Reference: 21 CFR Sec. 211.65, Equipment construction, and Sec. 211.67, Equipment
cleaning and maintenance.

There is no official agency preference for one material over another. Whatever material a
firm selects for its water for injection system must be suitable for the intended use. This holds
true for virtually any production equipment.

In the case of a WFI system, factors to consider in evaluating the suitability of the piping
would include interior smoothness, the ability to withstand high temperatures and pressures,
and the ability to hold up to sterilizing and sanitizing agents.

As a general matter, equipment surfaces that contact components, in-process materials, or

drug products must not be reactive, additive, or absorptive so as to alter the drug product's
safety, identity, strength, quality, or purity beyond its official or established requirements.

Contact for Further Info: John Levchuck,

HFD-322, 301-594-0095, e-mail: levchukj@fdacd.bitnet.

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 CIP Systems
Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of
contaminants in evaluating cleaning effectiveness?

Yes. Since the publication of the inspection guide on cleaning validation in 1993, a number of
studies have been published to demonstrate the adequacy of TOC in measuring contaminant
residues.
TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning
validation. In order for TOC to be functionally suitable, it should first be established that a
substantial amount of the contaminating material(s) is organic and contains carbon that can be
oxidized under TOC test conditions. This is an important exercise because some organic
compounds cannot be reliably detected using TOC.
TOC use may be justified for direct surface sample testing as well as indirect (rinse water)
sample testing. In either case, because TOC does not identify or distinguish among different
compounds containing oxidizable carbon, any detected carbon is to be attributed to the target
compound(s) for comparing with the established limit. Thus, a firm should limit 'background'
carbon (i.e., carbon from sources other than the contaminant being removed) as much as
possible. If TOC samples are being held for long periods of time before analysis, a firm
should verify the impact of sample holding time on accuracy and limit of quantitation.
References:

 21 CFR 211.67: Equipment cleaning and maintenance.

 21 CFR 211.160(b): General requirements (Laboratory Controls)

 USP 643 Total Organic Carbon

 Guide to Inspections of Cleaning Validation, 1993

Contact for further information:

Abi D'Sa, CDER
dsaa@cder.fda.gov
Brian Hasselbalch, CDER
hasselbalchb@cder.fda.gov

Is testing rinse solution alone enough to support residue determinations for cleaning
validation?

Reference: FDA Guide to Inspections of Validation of Cleaning Processes, July 1993

While it is understood that rinse samples are capable of sampling larger surface areas,
particularly ones which are difficult to access, for the purposes of cleaning validation, rinse
samples alone would not be acceptable unless a direct measurement of the residue or
contaminant has been made. One disadvantage of rinse samples is that the residue or
contaminant may not be soluble or may adhere to the equipment. Some firms use both swab
samples, where feasible, and rinse samples during the course of their cleaning validation.

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For routine equipment cleaning after validation, some firms may be able to justify use of rinse
samples to demonstrate the process continues to consistently clean the equipment.

FDA has compared rinse samples to that of a "dirty pot analogy." When evaluating the
cleaning of a dirty pot, the rinse water is not what is looked at to see if the pot is clean.

The purpose of cleaning validation is to demonstrate that a particular cleaning process will
consistently clean the equipment to a predetermined limit; the sampling and analytical test
methods should be scientifically sound and provide adequate scientific rationale to support the
validation.

Contact for further info: Patricia L. Alcock, HFD-322, (301)594-0095; e-mail:

alcockp@cder.fda.gov

What should investigators look for when inspecting a firm's cleaning validation program?

Reference: 21 CFR 211.67, Equipment cleaning and maintenance; 21 CFR 211.100, Written
procedures; 21 CFR 211.160, Laboratory controls; FDA Guide to Inspections of Validation of
Cleaning Processes, July, 1993

The objective of cleaning validation is to ensure that a specific cleaning process will
consistently clean to predetermined limits so as to prevent contaminants (product or cleaning
process related) from adversely affecting the safety and quality of the next product
manufactured.

As stated in the Guide to Inspections of Validation of Cleaning Processes, determine if firms

have a written, well established and validated cleaning program. Basic steps include the
development of a sensitive, accurate and precise analytical method for the determination of an
acceptable limit, something necessary for any analytical test method developed in
conformance with CGMPs. In addition, as discussed in the guide, determine if firms have and
follow specific written procedures as to how cleaning will be performed, as well as how the
cleaning validation will be conducted (including sampling procedures and analytical
methods). Determine if the validation protocol addresses different sampling surface types,
hardest to clean areas, and specific equipment, including utensils. FDA expects the validation
studies will be completed in accordance with written protocols and that the final validation
report will include the appropriate conclusions with management concurrence. Performing
testing of cleaned equipment, in accordance with written procedures, would be consistent with
21 CFR 211.67(b).

Contact for further info: Patricia L. Alcock, HFD-322, (301) 594- 0095; e-mail:
alcockp@cder.fda.gov

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Does FDA have impurities acceptance limits for cleaning validation and subsequent
cleaning verification?

Reference: 21 CFR 211.67, Equipment cleaning and maintenance; 21 CFR 211.176, Penicillin
contamination; International Committee on Harmonization (ICH) Guideline on Impurities in
New Drug Substances, Q3A, May, 1997

FDA has always been concerned with the issue of contamination and cross contamination.
Such contamination may include not only carry over from a previous product or residual
cleaning solvents, but also detergents and surfactants.

Except for penicillin, FDA has not established standard acceptance limits for cleaning
validation. Due to the wide variation in both equipment and products produced, it would be
unrealistic for the agency to determine a specific limit. In the CGMP context, however, firms
need to establish limits that reflect the practical capability of their cleaning processes, as well
as the specificity of the analytical test method.

We have found that some firms have incorrectly applied as their acceptance limit the 0.1%
impurity identification threshold as discussed in both the ICH impurity guideline and the
U.S.P. General Notices. This application of the 0.1% impurity threshold is inappropriate
because the limit is intended for qualifying impurities that are associated with the
manufacturing process or related compounds and not extraneous impurities caused by cross
contamination. It is important that acceptance limits reflect the capability of the cleaning
process.

When determining the acceptance limit, relevant factors generally include: (1) Evaluation of
the therapeutic dose carryover; (2) toxicity of the potential contaminant; (3) concentration of
the contaminant in the rinses; (4) limit of detection of the analytical test method; and, (5)
visual examination. While we suggest that these factors be considered, relying only on visual
examination would not be scientifically sound.

Contact for further info: Patricia L. Alcock, HFD-322, (301) 594- 0095; e-mail:
alcockp@cder.fda.gov

Has FDA identified an appropriate microbiological specification for monitoring critical

surfaces in an aseptic area used to make sterile drug products?

Reference: June, 1987 "Guideline on Sterile Drugs Produced by Aseptic Processing"

Yes. Product, container, and closure contact surfaces are known as "critical surfaces."
Microbiological monitoring of critical surfaces should yield zero colony forming units
(CFUs). Firms often express this action limit as <1 CFU. FDA's 1987 "Guideline on Sterile
Products Produced by Aseptic Processing" states:

"Equipment surfaces which contact sterilized drug product or sterilized container/closure

surfaces should, of course, be sterile. It is just as important in aseptic processing to properly

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validate sterilization processes applied to these equipment surfaces as it is to validate such
processes for the drug product and container/closures."

This standard can also be found in international publications such as the European Union's
"Manufacture of Sterile Medicinal Products" (Annex I to the European Union Guide to Good
Manufacturing Practice).

Contact for further information: Richard L. Friedman, HFD- 322, 301-594-0095; e-mail:
friedmanr@cder.fda.gov

Policy Questions on Cleaning Validation:

Reference: 21 CFR Sec. 211.67, Equipment cleaning and maintenance; and, Guide to
Inspections of Validation of Cleaning Processes, July 1993 (reformatted May 1994).

1) What is the level of detergent residue that would be acceptable to FDA? What is the
basis for arriving at this level, if any?

FDA has repeatedly stated that it is the firm's responsibility to establish acceptance limits and
be prepared to provide the basis for those limits to FDA. Thus, there is no fixed standard for
levels of detergent residue. Any residues must not adversely alter drug product safety,
efficacy, quality, or stability.

2) If the ability of a procedure to clean a piece of equipment made of a particular

material, such as 316 stainless steel, is shown to be acceptable and validated, can that
"material" specific cleaning procedure be used without "extensive" validation for other
pieces of equipment and compounds?

No. The design of the equipment is a major component of its cleanability. Therefore, firms
should have data that relate to a given piece of equipment.

Contact for Further Info: Anthony Lord, HFD-322, 301-594-0095, e-mail:

lord@fdacd.bitnet.

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