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1.1 Organizational and Management Responsibilities
This page will address various regulatory issues related to this section of the GMP Institute framework. Click below to view the issues that are relevant to you.
Do CGMP requirements apply to manufacturers of clinical supplies? Can such firms be inspected for CGMP compliance?
Reference:
Federal Register (43 FR 45013), September 29, 1978, preamble to the Current Good Manufacturing Practice
regulations, comment 49 (at 43 FR 45029), and
Guideline on the Preparation of Investigational New Drug Products, March, 1991.
The answer to both questions is yes. The Center for Drug Evaluation and Research may request that firms that make clinical supplies for Investigational New Drug (IND) trials be inspected for compliance with Current Good Manufacturing Practice (CGMP) regulations. Such inspections may be requested on a "for cause" basis, or with respect to "treatment INDs." The CGMP regulations do apply to investigational new drug products that are intended for administration to humans.
Investigational trials are typically divided into phases. Initially, at phase 1, trials usually involve small patient populations and are intended to evaluate the safety of the investigational product. At phase 3, trials usually consist of much larger patient populations and are used to evaluate both safety and efficacy.
As explained in the above guideline, the degree of CGMP control needed increases as the investigational trials near completion. An inspection of a phase 1 clinical supplies manufacturer would be expected to ensure that there are no added safety concerns based strictly on the failure to follow CGMP requirements, and that sufficient documentation is available so that the manufacturing process can be duplicated. For phase 3 trials, the degree of CGMP compliance would approach the control required for marketed products. For example, as explained in the guideline, at early clinical stages only limited process validation may be possible, and extensive in-process controls and intensive product testing may be used to demonstrate that a process run did, in fact, produce a finished product that meets all its specifications. As additional uniform batches are made under replicate conditions, we expect that more comprehensive validation will be conducted.
Investigational trials can begin 30 days after the submission of the IND to the agency unless a clinical hold is applied by the CDER review unit. Inspections of clinical supplies manufacturers which identify significant CGMP noncompliance may be a basis for a clinical hold; however, CGMP based holds are rare.
Contact for further information: Bruce W. Hartman, HFD-324, 301-827-0062; e-mail: hartmanb@cder.fda.gov
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 3) September, 1999.
Do the CGMP regulations require a contract laboratory to have a quality control unit for the operations it performs?
Reference:
21 CFR 210.2(b), Application of current good manufacturing practice
regulations;
210.3, Definitions;
211.22, Responsibilities of quality control unit
Yes. By definition, testing and quality control of drug products are part of manufacturing. At section 210.2, the regulations explain that where persons engage in only some operations subject to provisions of parts 210 and 211 (of Title 21), persons need only comply with those regulations applicable to the operations they perform. Therefore, a contract laboratory is subject to those portions of the CGMP regulations that cover activities it performs.
We would expect that many of the laboratory's activities would fall under Subpart I, Laboratory Controls, of the CGMP regulations. (Other provisions, such as those pertaining to personnel qualification, recordkeeping, facilities, and laboratory animals would also apply.)
The responsibilities of a quality control unit are pervasive in the CGMP regulations, and many lab functions require review and approval of a quality control unit. For example, per section 211.160, the quality control unit must review and approve test procedures and laboratory control mechanisms.
It should be clear, therefore, that section 211.22 applies to a contract laboratory and that the lab would have to have a quality control unit. However, that unit's responsibilities would only extend to the CGMP operations that the lab performs.
What's more, be aware that in smaller establishments, as might be the case in a contract laboratory, the responsibilities of a quality control unit may be assigned to as few as one or two individuals. In a larger organization, of course, an effective quality control unit may warrant a larger staff. This is consistent with the definition of quality control unit, at section 210.3(b).
Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 7, Number 1) March, 1999.
This same text is also reprinted in Framework sections 5.1,
5.5, 6.4.
If a contract laboratory obtains an OOS result, what are the CGMP responsibilities of the dosage form manufacturer and the lab with respect to follow up investigations?
Reference:
21 CFR 211.22(a & b), Responsibilities of quality control
unit,
21 CFR 211.160(b), General requirements [Subpart I—Laboratory Controls];
21 CFR 165, Testing and release for distribution
(sic);
Draft Guidance for Industry: Investigating
Out of Specification (OOS) Test Results for Pharmaceutical Production, 9/30/98;
21 CFR 211.194, Laboratory records
There are a number of possible scenarios under this question. Under CGMP, FDA would expect the contract laboratory to have a quality control unit. The lab's QC unit has the CGMP responsibility to ensure the analytical results obtained are accurate for the tested material. This means the contract laboratory needs to investigate any OOS result with the purpose of ascertaining such accuracy. This would be accomplished by ensuring that personnel performed the tests properly using: (1) The current validated analytical procedure; (2) correct reagents and reference standards; and, (3) equipment that has been properly maintained and calibrated.
There are basically two possible results of the lab's investigation.
1) If the lab determines the analyst made an error, or that instrument malfunction occurred, the test results may be invalidated. The analysis would be re-run according to the approved analytical method. The re-run test results would be considered the original results, and these results would be reported to the manufacturer. The lab does not have a CGMP obligation to report the initial (invalidated) results to the manufacturer; however, the lab must, per 211.194, retain the records pertaining to those initial results.
2) If the laboratory determines that there was no analyst error, and that no instrument malfunction occurred, then the results must be considered accurate and reported to the pharmaceutical manufacturer. In the event of outcome number two, the pharmaceutical manufacturer would have analytical results indicating the material does not meet its specifications. Under CGMP, an investigation must take place. The manufacturer is responsible for investigating the production process to determine if any mistakes were made--things to consider could include charge-in of components, mixing times, and quality of components. Storage conditions of the analyzed material, and the sampling method used also need to be reviewed to ascertain whether the tested material might not have been representative of the batch.
If the manufacturer's investigation fails to find a cause, it might also consider whether the contract laboratory is suspect (i.e., if perhaps the lab made an unrecognized error.) The CGMPs do not, however, explicitly require the manufacturer to extend its investigation to the lab's operations. However, it is considered CGMP for manufacturers to qualify their contract laboratories. At comment paragraph 94 of the September 29, 1978 CGMP revisions, 43 FR 45034, the agency said "[a] manufacturer does have a responsibility, however, to see that the outside laboratory used is qualified to do the work and that the work is performed satisfactorily."
As part of its investigation, the manufacturer might take the opportunity to requalify the contract laboratory, or may consider changing contract laboratories. Retesting could also be part of this process.
It must be stressed that in this situation the manufacturer has information that the batch does not meet its quality standards, and unless that information can be invalidated, it must be used to reach a batch disposition decision, namely, whether to destroy the batch, or reprocess it to bring it into compliance.
Contact for further information: Russ Rutledge, HFD-325, 301-594-0098, e-mail: rutledgec@cder.fda.gov
Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 7, Number 1) March, 1999.
This same text is also reprinted in Framework sections 4.3, 4.4, 5.2,
5.5, 6.3, and 7.2.
Is the employment of HIV infected workers in drug manufacturing facilities in conformance with CGMPs?
Reference:
October 17, 1986, Letter from Frank E. Young, M.D., Ph.D., Commissioner of Food and Drugs to 3M company
request for FDA's opinion;
21 CFR 211.28(d), Personnel responsibilities.
FDA's position was delineated in the Commissioner's letter which states in part:
"...a person infected with the AIDS virus should not be restricted a priori from working in a pharmaceutical... manufacturing facility... We are not aware of any epidemiological data that suggest any increased product safety risks associated with the employment of persons with AIDS under the conditions which would exist in... drug... manufacturing... based on the fact that all...evidence...indicates that bloodborne and sexually transmitted infections like AIDS would not be transmitted under normal conditions in the workplace."
The referenced section of the CGMP regulations that covers the suitability of personnel associated with the manufacture of drugs reads in part:
"Any person shown at any time (either by medical examination or 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..."
It is the manufacturer's responsibility to ensure that employees will not contaminate drug products with infectious agents.
Joyce E. Bloomfield, HFD-322, 301-594-0095; e-mail: bloomfieldj@cder.fda.gov
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 1) March, 1998.
Do the CGMP regulations prohibit a firm from outsourcing (contracting out) the functions of the quality control unit?
Reference:
21 CFR 210(3)(a),(b)(15), Definitions and
211.22 Responsibilities of quality control unit
No. The CGMP regulations do not prohibit a firm from contracting out the functions of the quality control unit, or any other function the regulations identify. It would therefore be inappropriate to list such QC unit outsourcing, per se, as an FDA 483 item.
The CGMP regulations define a quality control unit as "any person or organizational element designated by the firm to be responsible for the duties relating to quality control". The regulations incorporate by reference the definitions in the Federal Food Drug, and Cosmetic Act. The Act's definition of "person" includes an individual, partnership, corporation and association. Therefore, a quality control unit could be a corporation external to the drug product manufacturer.
More important than who takes on the QC role is the matter of how well the quality control unit performs its responsibilities as required in section 211.22 and elsewhere in the CGMP regulations. That should be the primary focus of inspectional attention when it comes to auditing the work of the QC unit. For example, the unit must have available to it adequate laboratory facilities for testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products. Those facilities may be at the manufacturing location or elsewhere, but the regulations mandate their availability to the QC unit.
Nonetheless, investigators who encounter firms that contract out the Q.C. unit should be aware of any aspect of the outsourcing that might impair the unit's ability to perform its many CGMP responsibilities. For example, if the contracted QC unit is remote from the manufacturing operations it is charged with monitoring, it might not be able to perform that oversight effectively and in a timely manner. Again, any FDA 483 item should speak directly to QC unit performance and not to outsourcing arrangements themselves.
Despite any division of CGMP activities, both the manufacturer and the outsourced Q.C. unit can be held responsible for introducing, or causing the introduction of, violative products into interstate commerce, each firm with respect to its actions. In addition, the violative products themselves would be subject to seizure.
Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 6, Number 1) March, 1998.
This text is also reprinted in framework sections 5.2,
6.4, and 7.2.
Do the CGMP regulations apply to a U.S. made cosmetic that is exported to a country where it is regulated as a drug?
Reference:
Section 201(g) of the Food, Drug and Cosmetic Act;
21 CFR 210.1, Status of current good manufacturing practice
regulations
No. The drug CGMP regulations apply to articles that U.S. law and regulation define as drug products. Drug CGMPs don't apply to articles that don't meet that definition, even if the articles are deemed, and regulated as, drugs outside the U.S.
Reprinted from FDA's Human Drug CGMP Notes, (Volume 5 Number 2), June, 1997.
Where are the requirements of [drug] 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)
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. |
| 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
Reprinted from FDA's Human Drug CGMP Notes, (Volume 4 Number 4), December, 1997.
Would pharmaceutical industry "teams" be compatible with drug CGMP regulations (e.g., regarding a q.c. unit's role, team approval of its own work, and product release)?
Reference: 21 CFR 211.122 (Responsibilities of quality control unit)
No, not if team implementation effectively usurps or countermands the function of the quality control unit. Overall responsibility of the quality control unit, especially with regard to approving specifications and releasing product for distribution, is clearly stated in the regulations.
Investigators who encounter "teams" in a pharmaceutical manufacturing facility should pay careful attention to the function of, and authority granted to, such units and the net effect that team autonomy may have on established standards and product quality.
For example, be wary of teams that may decide to implement production methods, analytical methods, or product specifications that differ from those in approved new drug applications.
Keep in mind the "so what" of team implementation. The existence of teams, per se, would not be a legitimate 483 observation because in some cases team implementation may not be at odds with the CGMP regulations and may, in fact, be beneficial. For instance, the quality control unit itself may theoretically be structured as a team. Production units may also include teams that could legitimately recommend process improvements to the q.c. unit (which ultimately evaluates and approves or disapproves of the suggestions). Production unit teams should not, however, independently put those changes into effect in the absence of q.c. unit review and approval.
Reprinted
from FDA's Human Drug CGMP
Notes, (Volume 3 Number 4), December, 1995.
This same text is also reprinted in Framework section 1.5
.