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211.22
(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.
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
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
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
This element of the regulations is extremely limited. The only stated responsibilities of personnel relate to personal hygiene. There are no assigned re-
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
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.
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
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.
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.