English: A few volumes of the Code of Federal Regulations (titles 12 to 26 out of 50 titles). The CFR is published each year as a set of softcover volumes which are updated on a quarterly schedule. Photographed at the law library of the UC Berkeley School of Law by user Coolcaesar on February 13, 2009. (Photo credit: Wikipedia)
An internal quality audit provides the firm with an opportunity to improve its systems and processes but it can also be a complete waste of time if no effective actions are taken to correct the deficiencies identified during the audit. It is the responsibility of the auditee, not the auditor, to determine appropriate actions based on the level of risk (critical, major, or minor) of the audit findings. The auditor, however, needs to assess the adequacy of the auditee’s response, and if the proposed corrective action plan seems feasible and reasonable, it should be accepted. If, however, the auditor has identified specific weaknesses in the action plan, these should be discussed with the auditee so that they may be addressed. An audit case study is presented below, analyzing the response to an internal audit observation, and discussing the elements of an effective corrective action plan.
Audit Case Study
An internal auditor is conducting a compliance audit of a FDA regulated pharmaceutical laboratory used for GMP testing. During the visit to the washing area, the auditor observes that the area is clean and tidy. When the auditor requests the cleaning logbooks, the lab manager states that the company’s cleaners are responsible for cleaning the laboratory. However, no cleaning records are maintained nor a standard operating procedure for cleaning of the washing area in the laboratory is available.
Consequently, the auditor cited the following observation: “Records for the cleaning of the floors in the washing area of the laboratory were not maintained in order to provide assurance that controls exist to prevent contamination across other lab areas as per 21 CFR 211.56, Sanitation”. No comments or objections were provided by the auditee at the exit meeting, and the audit report was issued within 20 days of completing the audit as per the firm’s standard operating procedure.
Subsequently, the auditee provided the following response with regards to the above audit observation: “The laboratory is not in scope of 21 CFR Part 211.56 since this is only for ‘Any building used in the manufacture, processing, packing, or holding of a drug product’ and does not include testing areas. No action is required”.
Is the auditee’s response deemed acceptable? Should the auditor close out this observation?
Minimum CGMP Regulatory Requirements
The auditee is not planning to take any corrective action, maintaining that the current Good Manufacturing Practices (cGMPs) are not applicable to the lab area. The initial response raises a concern about the adequacy of personnel qualification and the effectiveness of the firm’s GMP training program. The auditor should promptly reply to the auditee preferably in face-to-face discussions that the audit response is inadequate in that facility cleaning is a regulatory requirement, and the auditee must outline an effective corrective action plan that addresses the audit findings expressed by the audit report. Given the firm’s current audit response, the auditor can provide additional explanation of the current Good Manufacturing Practices regulations relating to the cleaning and disinfection of facilities, utilities and equipment. Moreover, the auditor can recommend that the audited department arrange a training session with the firm’s training department or a consultant to have specific GMP training related to their job functions. If the discussions do not result in an agreed corrective action plan proposal, then the matter should be escalated to the auditor’s management.
Title 21 Code of Federal Regulations 211.56 relates to the availability of an effective cleaning and sanitization program, and confirmation that the firm is following such program (Ref. # 1). The regulations are not descriptive as how the firm is to comply with this regulation. It is up to the firm to establish and follow a cleaning and disinfection program that meets the specific needs of a facility. The auditee has misinterpreted the GMP regulations in that 21 CFR Part 211.56 is applicable to the laboratory as per definition in Title 21 Code of Federal Regulations 210.3(B)(12): “Manufacture, processing, packing, or holding of a drug product includes packaging and labelling operations, testing, and quality control of drug products” (Ref. # 2). Cleaning and sanitization procedures should be written in sufficient detail, with respect to materials, equipment, process, and frequency, such that they are unambiguous. Failure to establish and implement a cleaning SOP and lack of cleaning records constitutes a failure in fundamental GMP requirements. Under Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act, a drug is deemed to be adulterated if the methods used in its manufacture, processing, packing, and holding, and the facilities and controls used for, do not conform to current good manufacturing practice, regardless of whether the product is actually deficient in some respect. Current good manufacturing practice regulatory provisions are intended to ensure the drug possesses adequate strength, quality, identity, and purity.
As described in the Preamble to Title 21, Subchapter C Drugs, the “CGMP regulations in Part 211 are intended to be general enough to be suitable for essentially all drug products, flexible enough to allow the use of sound judgment and permit innovation, and explicit enough to provide a clear understanding of what is required” (Ref. # 3). GMPs establish the minimum regulatory and legal requirements for quality and all aspects of drug production should meet that expectation. Moreover, employees are expected to understand GMPs, how they relate to their own areas of operation, and their overall impact on the company. Good Manufacturing Practice is the part of quality assurance that ensures that products are produced with the controls in place to consistently achieve quality standards appropriate for their intended use. Adherence to the GMP regulations is, however, not adequate to ensure that a pharmaceutical firm is in compliance. The firm must be constantly aware of what is current practice in the industry, and incorporate the necessary changes into its quality system. FDA encourages the use of technological advances in pharmaceutical manufacturing, as well as implementation of modern risk management and quality system tools and concepts (Ref. # 4).
Assessment of Audit Response
The audit response does not demonstrate an understanding and acknowledgement of the observation and if this was an FDA 483 Inspectional Observation, the FDA would have likely issued a warning letter after reviewing the audit response. The auditee did not make any commitment to correct the audit deficiency, i.e., ensure controls are in place to prevent cross-contamination across the lab areas, and the auditee’s response lacks sound judgment. The lab facility used for GMP testing purposes must be cleaned and disinfected on a regular basis according to a detailed standard operating procedure, in compliance with regulatory requirements as noted above. Implementation of a cleaning procedure is intended to limit viable and non-viable contamination. Moreover, all cleaning and disinfection activities must be documented at the time they are performed.
A well-reasoned, complete and timely audit response should assess the specifics of the observation, focusing on the regulatory requirement(s) associated with the observation and any system-wide implications, performing a root-cause analysis, and developing an action plan to achieve immediate, short-term, and long-term correction and to prevent recurrence. The corrective action plan should also identify who is responsible for that action along with the proposed implementation date. Lack of implementing corrective actions could be an indication of a lack of management commitment. The firm should treat the internal quality audit as if it was a FDA audit with senior management being informed on the progress of the corrective actions. Senior management must demonstrate commitment of the internal quality audit program by providing adequate resources and training to support the implementation of effective corrective actions.
Corrective action is defined by ISO 9000 standard as action taken to eliminate the cause of a detected nonconformity or other undesirable situation. Corrective action taken to address a quality problem or audit finding should include action to correct the existing quality problem or audit finding and prevent its recurrence. The full extent of the problem must be captured before the probability of occurrence, risk analysis, and the proper course of corrective action can be determined (Ref. # 5). If the real cause of the problem is not identified, then true corrective action is difficult to implement.
The auditee failed to maintain cleaning records for the washing area of the laboratory so in drafting the audit response, the auditee needs to consider the global implications of this observation. Are cleaning logbooks maintained in other areas of the laboratory such as in the Microbiology Lab and the Chemistry Lab? The auditee should address whether this audit finding is also a problem in other lab areas and research the root cause in order to eliminate the cause of this audit finding. There are various quality tools to help identify the possible cause(s) of a problem but a simple technique is the “five whys”. By asking the question “Why?” a number of times, the auditee peel away layers of symptoms to get to the real heart of an issue. When asking “Why” doesn’t yield any more useful information, the auditee has identified a potential root cause. Sometimes the auditee may reach a root cause after two or three whys, and sometimes the auditee may have to go more than five layers down.
The following is an example of finding the root cause for not maintaining cleaning records using the “five whys” analysis method.
- “Why records for the cleaning of the floors in the washing area of the laboratory are not maintained?” Because lab personnel are not responsible for cleaning of this lab area. The company’s cleaners are responsible for cleaning and documenting their activities.
- “Why are the cleaners not documenting the cleaning activities in a logbook?” Because there is no standard operating procedure (SOP) for cleaning of the lab’s washing area.
- “Why is there no cleaning SOP for this lab area?” Because lab management has not written an SOP for their area. The cleaner’s management has pointed out to lab management to write an SOP.
- “Why has a cleaning SOP not written and followed?” Because lab management has not taken ownership in authoring a cleaning SOP. This is not a priority for them.
- “Why lab management hasn’t taken ownership of authoring a cleaning SOP?” Because lab management is busy creating and revising SOPs for other lab areas and don’t think that cleaning of this lab area is a current Good Manufacturing Practice (cGMP) requirement.
The above example points out the auditee’s lack of understanding of cGMP regulations as a root cause for not maintaining cleaning records. It implicates the firm’s training program as being inadequate and consequently, the auditee should develop a corrective action plan that includes GMP training of lab personnel related to their job functions. In addition, asking “Why?” three times revealed a cause, in that there is no SOP to outline the responsibilities and tasks of laboratory and cleaning personnel. Thus, the corrective action plan should also include the creation of a cleaning SOP as well as another action to capture the training of laboratory and cleaning personnel on this new SOP. Specific responsibilities and dates for the corrective actions also have to be identified as well as include corrective action checks for appropriateness, adequacy and effectiveness.
Audit Case Wrap-Up
When an audit finding such as failure to maintain facility cleaning records is identified during an internal quality audit, it is the auditee’s responsibility to take timely and appropriate action to comply with the regulatory requirements and company’s policy. The auditor can clarify what is necessary to achieve compliance but cannot dictate how compliance is to be achieved. Corrective action must address the real cause of problem and prevent recurrence of the same problem. Using the “five whys” analysis method can help the auditee move past symptoms and understand the true root cause of an audit finding. Auditors must reject weak audit responses explaining the possible ramifications if the deficiency is not corrected, otherwise auditors will repeatedly report the same or closely related audit finding. Effective corrective actions can result in system and process improvements and enhanced system and process understanding.
REFERENCES
- U.S. Food and Drug Administration, 21 CFR 211.56 Sanitation, http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr;sid=1918dfd27b3108cbc392ceb0ac8f93fa;rgn=div5;view=text;node=21%3A4.0.1.1.11;idno=21;cc=ecfr#21:4.0.1.1.11.3.1.7; accessed on 07 August 2012.
- U.S. Food and Drug Administration, 21 CFR 210.3 Definitions, http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr;sid=1918dfd27b3108cbc392ceb0ac8f93fa;rgn=div5;view=text;node=21%3A4.0.1.1.10;idno=21;cc=ecfr#21:4.0.1.1.10.0.1.3; accessed on 07 August 2012.
- U.S. Food and Drug Administration, Title 21, Subchapter C—Drugs: General, Docket No. 75N-0339, Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding, March 28, 1979, http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM095852.txt; accessed on 07 August 2012.
- U.S. Food and Drug Administration, Pharmaceutical cGMPs for the 21st Century—A Risk-Based Approach, September 2004, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/ucm137175.htm; accessed on 07 August 2012.
- U.S. Food and Drug Administration, Inspection Guides, Corrective and Preventive Actions (CAPA), http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm170612.htm; accessed on 07 August 2012.
Related articles
- Canadian GMP Regulations Applicable to Procedures (validationquality.wordpress.com)
Aris Koumandaros
Comments on: "To Clean Or Not To Clean—An Audit Case of Misinterpreting the Good Manufacturing Practices" (1)
[...] To Clean Or Not To Clean – An Audit Case of Misinterpreting the Good Manufacturing Practices (validationquality.wordpress.com) [...]