3

Organization and Personnel

(Subpart B)

211.22

RESPONSIBILITIES OF QUALITY CONTROL UNIT

(a) There shall be a quality control unit that shall have the responsibility
and authority to approve or reject all components, drug product containers,
closures, in-process materials, packaging materials, labeling, and drug products, and the authority to review production records to assure that no errors
have occurred, or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting
drug products manufactured, processed, packed, or held under contract by
another company.
(b) Adequate laboratory facilities for the testing and approval (or rejection)
of components, drug product containers, closures, packaging materials, inprocess materials, and drug products shall be available to the quality control
unit.
(c) The quality control unit shall have the responsibility for approving or
rejecting all procedures or specifications impacting on the identity, strength,
quality, and purity of the drug product.
(d) The responsibilities and procedures applicable to the quality control unit
shall be in writing; such written procedures shall be followed.

The regulations clearly assign to the quality control (QC) unit responsibility
for approval or rejection of components, in-process materials, and products. At
one time the attainment of quality standards relied heavily on testing and inspecCopyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

tion by QCquality was inspected into components and products. Since QC

testing is usually after the event, and also relies on the evaluation of a relatively
small sample, this approach was seen by some as both ineffective and inefficient.
It also tended to separate accountability for production and quality.
The CGMPs focus all responsibility for quality onto the QC unit. There
are no defined responsibilities for production managementunlike the European
and World Health Organization (WHO) guidelines (see Chapter 21), which define
both separate and joint responsibilities for these functions. This latter approach
more clearly emphasizes that the consistent achievement of quality standards
requires a team effort.
A more effective approach has been to design quality into products during
the development phase and then to build in additional assurance during production. The regulations support this approach. New products are usually developed
by a research and development unit, which will draft appropriate specifications.
These must then be reviewed and approved by QC, which serves as an independent double-check on this important parameter.
Within the production operations all quality-impacting procedures and systems are to be approved by QC. Typically, these include such procedures as
standard operating procedures (SOPs), process validation protocols, supplier certification protocols, complaint handling, process control procedures, and even
design of buildings. Since some of these systems are owned by other functions, it is essential that QC have effective procedures to ensure that such systems
are reviewed in a timely manner and that changes cannot be introduced without
approval. During 1985 and 1986 several companies had serious problems associated with changes in formulations and manufacturing processes, which then failed
to comply with requirements of NDA and ANDA documentation. These discrepancies resulted in halting of distribution and recalls, with significant loss of
revenue to the companies involved. Some of these situations occurred because
economies and expedition overwhelmed inadequate approval systems.
QC is also responsible for approving or rejecting labeling. This responsibility lies in two areas. First, new or modified labeling should be reviewed to ensure
that it complies with the ANDA, NDA, OTC monograph, or other official requirements that are applicable. This checking may be delegated to other functions,
but QC must assure that the checkers are qualified to perform their function and
that they have done so. Second, incoming labeling supplies are to be evaluated
to assure they are correct. These responsibilities do not apply to promotional
literature.
The approval/rejection responsibility also applies to operations contracted
out to other companies. This does not necessarily require any additional or duplicate testing. Provided the contractor has adequate procedures and is in full compliance with CGMPs, it should only be necessary to compare the test data with
specification and with data from previous batches to identify trends.
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Confirmation of the adequacy of the contractor will normally involve an

audit and testing in parallel for a period of time; periodic reevaluation should
occur.
The regulations require adequate laboratory facilities to be available to the
QC unit. This clearly allows use of outside laboratories where necessary, but
these should be comprehensively evaluated before use.
The FDA emphasis for QC is on release and/or rejection authority. While
this is important, the regulations ignore the ever-increasing importance of other
activities by QC that provide positive impact on quality. These include creation
of quality awareness, involvement in product design and development, design
and provision of quality training, facilitation for quality improvement, analysis
of quality trend data to identify improvement needs and opportunities, identification of quality metrics, and collection and dissemination of quality benchmarking
data. These additional activities all enhance the awareness and involvement of
senior management, thereby assuring greater emphasis and attention to quality
by all functions.
No guidance is provided about the actual organization of the QC department, and a wide range of viable alternatives are in effect. One of the simplest,
but very effective, is the subdivision into quality controlall inspection and
testing and quality assuranceall systems and procedures including batch review
and audit. With the increased reliance on non-QC personnel for quality-related
activities, such as in-process control and customer complaint coordination, the
role of the quality assurance (QA) unit has become critical. The regulations essentially expect the QC/QA function to provide an independent policy-type role, to
monitor the entire production process from purchasing of materials to distribution
and use of the product. The function should also be proactive by evaluating data
on processes, materials, and suppliers and recommending changes that will improve efficiency and consistency. QC should be a resource that plays a positive
role in improving profitability. More will be said about this in future chapters.
The responsibilities of the QC unit with respect to acceptance/rejection has
led to extensive discussion on organizational reporting lines. Obviously, the QC
function cannot report to the person who is held directly accountable for production. This could result in undue pressure being brought to bear to release marginal
materials or products. In an enlightened company where everyone is fully aware
of the importance of quality and committed to its achievement, this should not
be an issue. However, some companies have gone a step further by insisting that
the QC unit should report outside of the plant operations to a group QC function
or other scientific or technical function. This arrangement certainly provides an
added level of independence and appears to be favored by the FDA. However,
as previously expressed, quality standards cannot be assured by a police approach. With a totally independent QC unit, there is likely to be a chance of
divided responsibilityproduction to produce and QC to confirm quality. It is
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

Figure 1 Typical plant organization.

preferable that the entire plant operate as a quality-aware team, every individual
being expected to perform his or her job in such a manner as to achieve the
quality standards. QC then becomes a supporting resource. This is more likely
to occur if the QC unit reports directly to the leader of the plant teamthe plant
manager. An adequate degree of independence can be incorporated into the organization by having a clearly defined functional reporting (dotted line) relationship to a suitable scientific professional in the organization (Figure 1). This
approach encourages a team spirit, which will result in a higher and more consistent achievement of quality standards. Even the review of potential accept/reject
decisions should be handled by the management team so that everyone is involved
in understanding the cause of the problem, the implications of the ultimate decision, and the need for appropriate corrective action. In the event that the team
is in favor of acceptance when QC consider rejection to be correct, the final
decision resides with QC; the plant manager cannot override.
Some companies have taken the team approach a stage further by the introduction of self-managed work teams. The various functions or disciplines are
incorporated into the team, which can be responsible for all its operational requirements. This can include, in extreme cases, hiring of new team members,
discipline, allocation of wage increases or bonuses, work scheduling, product
testing, and release/rejection decisions. In these instances there still needs to be
an independent QC evaluation for final release/rejection to satisfy the regulations.

211.25

PERSONNEL QUALIFICATIONS

(a) Each person engaged in the manufacture, processing, packing, or holding

of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions.
Training shall be in the particular operations that the employee performs and
in current good manufacturing practice (including the current good manufacCopyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

turing practice regulations in this chapter and written procedures required by

these regulations) as they relate to the employees functions. Training in current good manufacturing practice shall be conducted by qualified individuals
on a continuing basis and with sufficient frequency to assure that employees
remain familiar with CGMP requirements applicable to them.
(b) Each person responsible for supervising the manufacture, processing,
packing, or holding of a drug product shall have the education, training, and
experience, or any combination thereof to perform assigned functions in such
a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess.
(c) There shall be an adequate number of qualified personnel to perform
and supervise the manufacture, processing, packing, or holding of each drug
product.

The development and training of employees, at all levels, should be seen as

a continuous process (Figure 2) in which performance appraisal plays a key role.
The GMP regulations do not attempt to define the education, knowledge,
skills, or experience required for the different types of job within a pharmaceutical company. This is significantly different from the European and WHO guidelines, which do specify the knowledge and experience requirements for those
individuals designated as responsible for production and quality. The consistent
achievement of quality standards requires understanding of, and compliance with,
established procedures. Consequently, initial screening should select only those
individuals who have such basic skills as reading, writing, and numeracy. An
employee who cannot understand written instructions will find it difficult to fol-

Figure 2 Training and development cycle.

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

low procedures, an inability to write coherently will inhibit the recording of atypical situations, while a lack of numeracy could make it impossible to perform
certain in-process testing such as statistical process controls. For certain positions
color vision may also be important, and some 10% of the population have some
degree of color vision problem.
In addition to these basic skills required by every employee, there are specific requirements for certain jobs, such as higher qualifications in engineering,
chemistry, microbiology, etc. In order to define these additional requirements it
is important to perform a knowledge and skills assessment for each job category.
Because of the changing environment in which we work it is essential to reevaluate these needs from time to time.
Preemployment screening for the purpose of identifying potential security
risks is of special importance when the pharmaceutical manufacture involves the
handling of controlled substances. This screening must not only include careful
scrutiny of the potential employees personal and previous employment references, but also whatever review of criminal background as may be possible. The
Drug Enforcement Agency (DEA) position on employee screening is set out in
21 CFR 1301.90. Subsequent parts, 1301.91, 1301.92, and 1301.93, indicate the
tenor of the employers responsibility as it must be conveyed to the employee
and describe the sources of information to be used in employee checks.
While the dangers of insecurity with respect to controlled substances are
of concern to the DEA as they may involve criminal acts and frustrate accountability, the effect of loss or diversion of any ingredient or product will reflect as
a CGMP failure.
Once accepted for employment, the initial, or induction, training takes
place. This usually occurs on the first day and includes background on the industry, the companyits policies and proceduresand some fundamentals on the
importance of the employees role to the health and well-being of the ultimate
consumer. This session tends to be somewhat general in nature and should be
followed by the more specific basic training.
Basic training will usually take place over a period of time during which
the new employee will be closely supervised. During this stage the employee
must be fully trained in all relevant techniques associated with the equipment
involved and fully understand the procedures to be followed, and must be aware
of the potential problems that can be created by nonadherence to these procedures. Such problems could include production of substandard material resulting
in rework or rejection if identified in-house or in potential consumer harm, litigation, and recall if not detected until in the marketplace. All these consequences
add cost and some also have the potential to erode consumer confidence.
Training programs must include appropriate evaluation steps. These will
usually involve some type of evaluation at the end of each module followed by

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

on-the-job appraisal to confirm that the lessons learned have been put into practice. Repeat training should be initiated when necessary. The regular employee
performance appraisal process should also identify further training needsas
refreshers to existing knowledge and skills, to meet the changing needs of the
operation, or in preparation for a job change requiring additional skills.
Education and training records must be maintained and kept current; FDA
inspectors may ask for confirmation of adequate training.
The responsibility for training of employees should reside with departmental management. However, the QC department should monitor or audit to ensure
that the appropriate training has been given. This could include review of training
module content and also of training records. Additionally, QC staff themselves
are likely to be involved in providing some of the training.
Training, although essential, is more effective in a supportive environment.
If management, by example, demonstrate that compliance with procedures is important and encourage participation in improvements, then training will be put
into practice. The acknowledgment of achievement by public recognition or remuneration, often termed positive reinforcement, has a significant impact. The
demonstration by example is further illustrated in a later section.

211.28

PERSONNEL RESPONSIBILITIES

(a) Personnel engaged in the manufacture, processing, packing, or holding

of a drug product shall wear clean clothing appropriate for the duties they
perform. Protective apparel, such as head, face, hand, and arm coverings,
shall be worn as necessary to protect drug products from contamination.
(b) Personnel shall practice good sanitation and health habits.
(c) Only personnel authorized by supervisory personnel shall enter those areas of the buildings and facilities designated as limited-access areas.
(d) Any person shown at any time (either by medical examination or by
supervisory observation) to have an apparent illness or open lesions that may
adversely affect the safety or quality of drug products shall be excluded from
direct contact with components, drug product containers, closures, in-process
materials, and drug products until the condition is corrected or determined
by competent medical personnel not to jeopardize the safety or quality
of drug products. All personnel shall be instructed to report to supervisory
personnel any health conditions that may have an adverse effect on drug
products.

This element of the regulations is extremely limited. The only stated responsibilities of personnel relate to personal hygiene. There are no assigned re-

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

sponsibilities to comply with defined procedures or to advise management of

deviations or problems.
The wearing of uniforms for manufacturing and control operations is not
mandated, only that clothing shall be clean and appropriate for the duties being
performed. In defining what clothing is appropriate it is necessary to consider
the end purpose. For example, it would be inappropriate to require hair covering
to protect the product from the inadvertent ingress of hair and then to allow
employees to wear clothing that incompletely covered the hair, did not cover
beards or moustaches, or left the arms uncovered. Yet such situations do exist.
The use of plant uniforms is generally a more satisfactory way of maintaining adequate standards of dress and the following guidelines may be applied:
1. A sufficient amount of clean uniforms is provided so that changes can
be made at an adequate defined frequency or whenever they became
soiled.
2. Washing and sanitation procedures should be checked to confirm their
effectiveness.
3. Employees in special clean areas should wear only lint-free garments
to prevent shedding.
4. Garments should be designed and use material that maximizes personal
comfort.
5. The range of clothing available would normally include:
a. Hats or hair cover
b. Beard and moustache covers
c. Coverallspreferably with no pockets, or pockets suitably designed
to prevent articles falling out
d. Disposable gloves
e. Foot covers or shoes
f. Masks
g. Safety glasses or goggles
h. Appropriate clean-room suits for sterile areas
6. Employees should be shown how and when to wear the appropriate
clothing.
7. Work clothing should not be worn outside of the appropriate plant area,
and changing rooms should be available.
The continued wearing of such clothing in cafeteria areas during breaks
should also be evaluated. Food particles in and on clothing can introduce bacterial, fungal, and yeast contamination. Obviously, operators in sterile areas will
change prior to leaving the area, and this may be desirable for some other areas,
especially to minimize the potential for cross-contamination.
Compliance with the requirements that production processes should not

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

be exposed to employees who are sick starts with the preemployment medical
examination. This will normally include some medical history, chest x-ray, Wassermann test, and tuberculosis test. Employees should require a fitness statement
from a physician, either company or personal, for return to work after sick leave
greater than a specified period (one week). Annual medical reexaminations are
sometimes required. Because some locations have stringent concerns as to invasions of employee privacy, personnel should be guided by legal advice that is
current. There should be a liberal policy for those who feel fit for work but show
symptoms of the common cold or other nondisabling illness. Employees will be
reluctant to report these conditions if they are punished by being sent home,
having their pay reduced, or being told to continue work since it doesnt really
matter. Ideally, these employees should be allowed to work at tasks in which
they cannot contaminate products and at their usual rate of pay.
Separating an ill worker or one with open lesions from the product by use
of gloves, masks, or special clothing is not recommended. The discomfort involved in their use tempts the worker to discard them when not being observed.
The requirement of this section to report adverse health conditions will not be
effective unless a set of specific conditions to be reported is provided. Again, be
guided by current legal advice as to the substance and receipt of such information.
The primary objective of this section of the regulations is to protect the
product from potential contamination from personnelparticulate matter including hair, fibers, and outside dirt, cross-contamination carried on clothing from
other processes, microorganisms shed from skin and from the mouth and nose.
However, an employer also has a responsibility to protect the employee from
unacceptable exposure to the materials being handled, many of which have physiological properties. Where potential exposure is to very potent materials, testing
of blood or urine samples may be warranted. Wherever possible, barrier or containment facilities or equipment should be used to protect personnel from extremely hazardous materials. The use of masks or breathing equipment should
only be used as the sole precaution in rare circumstances or for less hazardous
materials.

211.34

CONSULTANTS

Consultants advising on the manufacture, processing, packing, or holding of

drug products shall have sufficient education, training, and experience, or
any combination thereof, to advise on the subject for which they are retained.
Records shall be maintained stating the name, address, and qualifications of
any consultants and the type of service they provide.

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

It is difficult to appreciate the need for this section. It is highly unlikely

that a company would spend money to employ a consultant who was inadequate
in education, training, or experience. Additionally, company management are
accountable for any effects resulting from implementation of advice from consultant. However, this section provides a means to educate the agency as to the
identity of the consultants where the FDA inspection reveals significant deficiencies.
Note that under Section 211.122(c) the QC unit must approve the qualifications of a consultant whose work may impact on the identity, strength, quality,
or purity of a drug product. A more appropriate and useful topic would have
been the use of contractors for either laboratory or production operations.
We therefore transmit some advice on that point.
The use of contractors for either laboratory or production operations has
grown to a fairly common practice in pharmaceuticals and device manufacture.
The labeler and distributor of the final finished product, in the absence of contrary
agreements between the parties, bears primary commercial, civil, and regulatory
responsibility in keeping with established legal theory and business custom in
the United States and Europe.
Because the regulatory agency sees so much activity along the lines, they
have made available compliance policy guidelines. Following, therefore, we have
included CPG150.16, which typifies their view and attaches to Status and Responsibilities of Contract Sterilizers Engaged in Sterilization of Drugs and Devices. This touches upon Registration and all that connotes as well as the
CGMPs. The reader should consider it also with respect to Chapter 11 below.
Following study of this chapter, it might be helpful for staff review, to
discuss specific guides provided by the FDA to their field staff and others, that
are pertinent as Regulatory Action Guidance.

COMPLIANCE POLICY GUIDELINES

Sec. 100.550 Status and Responsibilities of Contract
Sterilizers Engaged in the Sterilization of Drugs
and Devices (CPG 7150.16)
BACKGROUND:
Questions have been raised as to the responsibilities of a contract sterilizer under the Food,
Drug and Cosmetic Act. The questions concern registration requirements under Section
510, Agency inspectional policy, documentation and validation requirements, and responsibilities of the parties to the contractual agreements.

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

DEFINITION:
For the purposes of this guide the following definition will apply:
Contract Sterilizer. An establishment that provides a contractual service intended to sterilize an FDA regulated product.
POLICY:
1.

2.

3.

4.

5.

6.

Responsibility of Contract Sterilizers:

Contract sterilizers are responsible for conformance with the portions of the
current Good Manufacturing Practice (CGMP) regulations that pertain to the
services they provide.
Registration:
Each contract sterilizer of a drug or device product must register as set forth
under section 510 of the Act.
Documentation:
The finished drug or device manufacturer should maintain, as part of the master
production and control record, or reference, written process specifications and
documentation of the validation of the sterilization process conducted by the
contract sterilizer. The finished drug or device manufacturer should also maintain, or have readily available, copies of the contract sterilizers batch production records.
The contract sterilizer must maintain documentation of validation and the written process and production specifications and procedures necessary to assure
the process is adequately completed. Contract sterilizers are also responsible
for completing and maintaining batch records of all operations performed.
Inspections:
Contract sterilizers, as drug or device processors, are subject to the biennial
inspection requirements of the Act.
Contractual Agreements:
The contractual agreement should specify which establishment will execute
various functions. In general, the establishment which executes a given function
will be primarily responsible for the CGMPs which apply to that function.
Sterilization Process Validation:
Sterilization processes are required by the CGMPs to be validated. The validation may be conducted by either the finished drug or device manufacturer or
the contractor. The finished drug or device manufacturer has ultimate responsibility for assuring that the finished drug or device meets sterility specifications
and is processed under adequate CGMP controls. The contractor who offers a
sterilization process has responsibility to assure the process is effective and
that adequate GMP controls are established and implemented. Therefore both
parties are responsible for validation and liable to the extent that they have
contributed to the noncompliance. The absence of an agreement does not remove this responsibility for either party.

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

NOTE: For licensed biologicals, the Center for Biologics Evaluation and Research
holds the final manufacturer responsible for all production processes, including validations
of sterilization performed under contract, whether or not the contract so states.
REGULATORY ACTION GUIDANCE:
In adverse findings are encountered during an inspection, the appropriate Center should
be notified. In addition, the districts that have firms using the services of contractors outside the district should be advised of any adverse finding.
In considering regulatory, voluntary, or administrative action, the agency will regard the manufacturer as primarily responsible for assuring the compliance of the medical
product. However, the contract sterilizer and the manufacturer will be held jointly responsible for those 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 GMPs.
Should regulatory action be generated as a result of inspection of the contract sterilizer,
both parties should receive copies of all correspondence.
* Material between asterisks is new or revised *
Issued: 3/1/84
Revised: 8/31/89, 3/95

EXAMPLES OF OBSERVATIONS FROM FDA 483

CITATIONS
1. There was insufficient personnel for performance of the quality control
activities in that there are no approved written procedures to include cleaning of
manufacturing and laboratory equipment, maintenance and calibration of laboratory equipment, label procedures for quarantine materials, stability program,
GMP training of all personnel.
2. The GMP training program is inadequate in that it does not define the
type, level, and schedule of GMP training required for various employee positions; production employee training consists of a review of SOPs and on-the-job
training.

SUGGESTED READINGS
1. J. Litterer, Organizations: Structure and Behavior, Wiley, New York, 1968.
2. E. Murray, Motivation and Emotion, Prentice-Hall, Englewood Cliffs, NJ, 1965.
3. E. Schein, Organizational Psychology, Prentice-Hall, Englewood Cliffs, NJ, 1965.

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

4. F. Delmore, Industry Associations and Self-Regulation, Food, Drug, Cos. Law J.,
24(11):557564, 1969.
5. J. Saengen, The Key To Quality Programs, Bull. Parent. Drug Association, 23:197
285, 1969. This is an excellent description of one companys quality assurance program.
6. S. H. Willig, Drug Abuse in Industry and Business 1971, Symposium Enterprises.
7. B. J. Donato, Kenneth A. Olsen, Vol 11, No. 2 (July 1994) Food Drug Cosmetic
Legal Liability For Regulatory Affairs Professionals . . . and Medical Device
Law Digest.
8. R. H. Clark and K. L. Dimond, Compliance Plan: A Drug Companys first line
of defense . . . Vol 13, No. 2, May 1996, Food, Drug, Cosmetic and Medical Device
Law Digest.
9. See also Drug Free Work Place Requirements, Fed. Register, Tues Jan 31, 1989.
10. Employee Benefits Bulletin. A Review and Analysis of Recent Developments, Sept.
1999. Alan M. Koral. Free Copies Available. 805 Third Ave. N.Y., NY. 10022.

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.