OR WAIT null SECS
Twelve lessons of what to do and what not to do to avoid quality problems.
The pharmaceutical and medical device industries can learn from Toyota's recalls to avoid their own "runaway" quality problems. The same quality problems that surfaced during the recall of nearly eight million vehicles from the world's largest automaker have a corresponding counterpart in the pharmaceutical, biotech, and medical device industries.1
(MONTY RAKUSEN/CULTURA /GETTY IMAGES)
The quality systems currently used in FDA-regulated industries have their origins in the military standards used in the aerospace industry and the quality management systems of the International Organization for Standardization (ISO). At the heart of any good quality program is the universal goal of making a product that is fit for its intended use, safe, and reliable, and that consistently meets product specifications and customer expectations. Consequently, there is considerable overlap in the systems used to ensure automobile and pharmaceutical product quality.
Topics as they relate to the Toyota recalls and the corresponding pharmaceutical lessons are discussed in this article.
Robert N. Borghese
1. MANAGEMENT MUST TAKE RESPONSIBILITY
Toyota example: Toyota's Chief Executive Officer (CEO) Akio Toyoda took full responsibility and apologized before the US Congress on February 24, 2010.2
Lesson for Pharma: The top executive is ultimately responsible. That is why the FDA addresses warning letters to the top executive.
2. KEEP YOUR QUALITY PRIORITIES RIGHT AND MAKE THEM CLEAR
Toyota example: Toyota's CEO admitted that the company began to put efficiency above quality.
"I would like to point out here that Toyota's priority has traditionally been the following: first, safety; second, quality; and third, volume," said Toyoda. "These priorities became confused...we pursued growth over the speed at which we were able to develop our people and our organization..."3
These statements suggest that the understanding of priorities and how to implement them was uneven within the organization.
Lesson for Pharma: The goals of the company—in the form of its mission statement, quality policy, and priorities—must be communicated to and understood by all employees. Proof of effective communication is the ability of each employee to paraphrase the goals of the company in his or her own words if asked.
3. THE CORPORATE CULTURE OF QUALITY MUST EXTEND WORLDWIDE
Toyota example: Toyota's much-vaunted corporate culture of quality was not exported to manufacturing sites around the world. The challenges of rapid growth and international marketing contributed to the lack of uniform worldwide quality.
Lesson for Pharma: The quality management systems described in the FDA's Quality System Regulation (21 CFR 820), ISO 9001 (Quality Management System), and ISO 13485 (Quality Management System for Medical Devices) are broadly overlapping in their requirements and are applicable across international borders. Regulatory authorities do not recognize rapid growth as an excuse for non-compliance. The take-home lesson is: Do not grow faster than the establishment of quality systems permit.
Furthermore, the corporation's quality responsibilities are not limited to work performed within the corporation; they extend to vendors and contract manufacturers. Therefore, vendor audits and the use of approved vendor lists are critical for success.
4. PAY PROPER ATTENTION TO COMPLAINTS
Toyota example: Toyota is alleged to have ignored or minimized thousands of early reports of sudden acceleration in its vehicles.4
Lesson for Pharma: Every complaint must be recorded and analyzed, and any complaint that involves a product specification must be investigated. Accumulating data must be analyzed for trends and preventive action must be taken to prevent a problem from getting worse.
There is a misconception in the pharmaceutical industry that some threshold number of complaints must be received before there is need for a recall. Not so. Even one valid complaint can trigger a recall. If the complaint is credible, serious, and unexpected (i.e., it does not appear in the product label), it would behoove the firm to immediately investigate, sending a technical person to the site of the complaint if necessary.
In a real life example, my quality control laboratory received a high assay on an antimicrobic raw material and a complaint was called in to the pharmaceutical company client. The next day, there were two technical representatives from the pharmaceutical company at my door—even though my laboratory was 1,200 miles away! They took the complaint seriously because a valid high assay would have a serious adverse effect on patients. As it turned out, the discrepancy in assays was attributed to a difference in testing methodologies, demonstrating the important QC lesson that you cannot separate laboratory results from the methodology used.
5. SERIOUS ADVERSE EVENT REPORTING MUST BE HANDLED WITH DILIGENCE
Toyota example: At the time of this writing, 39 deaths have been attributed to runaway Toyotas.5
Lesson for Pharma: The FDA has specific regulations to handle serious adverse drug experiences on marketed products. In the case of pharmaceutical or biological products, the recipient of a serious and unexpected adverse drug experience has 15 calendar days to report it to the FDA.6 The industry faces its greatest challenge to meet the reporting deadline because international adverse event reporting sometimes is delayed by time and holiday differences. Strict adherence to allotted review times and adequate global adverse event handling systems are essential.
6. CONDUCT A THOROUGH SITUATION ANALYSIS BEFORE MAKING PUBLIC STATEMENTS
Toyota example: During its handling of the recalls, Toyota's managers made inconsistent and sometimes contradictory statements, suggesting that they had not analyzed the situation carefully before they began speaking about it.
Lesson for Pharma: When a major problem begins to surface, a situation analysis should be prepared to pull together all of the information and analyses for management review and action. The company's conclusions must be supported with a well-thought-out rationale that will avoid inconsistent statements. Don't get caught like a deer in the headlights, unable to respond effectively and demonstrate as clear an understanding of the problem as available data permits.
7. PERSIST UNTIL YOU IDENTIFY THE ROOT CAUSE OF THE PROBLEM
Toyota example: Toyota defined the problem (unexpected acceleration, faulty braking) and then investigated, but may not have gotten to the root cause. Problems were blamed on faulty floor mats and sticky gas pedals; however, there have been reports that the problem continued after the "fix," which suggests that the root cause may not have been identified.7
Lesson for Pharma: Promptly define the problem, investigate, and get to root cause by performing a root cause analysis (RCA). If you do not get to the root cause, there cannot be an effective corrective or preventive action (CAPA).
8. WHEN ADDRESSING A PROBLEM, INCLUDE ALL AFFECTED PRODUCTS
Toyota example: Toyota knew about those problems years ago and made some fixes on models sold in Japan, but delayed addressing the problems on other cars.8
Lesson for Pharma: Effective CAPA includes addressing all other products that may be affected. For example, if one drug or one model of medical device is judged to have a deficiency, all of the drugs in that class or all medical devices in the same family must be examined as part of the investigation.
9. DON'T HESITATE TO RECALL, BUT BE PREPARED BEFORE YOU DO IT
Toyota example: Toyota is in the midst of one of the largest automobile recalls in history. Although a recall obviously is an unfortunate occurrence that will adversely affect customer confidence, a firm-initiated recall is actually a responsible corporate action. It is the responsible firms that initiate recalls.
Lesson for Pharma: The FDA has specific recall regulations regarding a firm-initiated recall.9 A recall will generate a lot of publicity, so a firm should be prepared with a solid policy and procedure to handle the details of the recall event. If not handled properly, a recall can easily spin out of control. A high profile recall will have some unpleasant consequences, such as opportunists trying to cash-in. Be prepared.
The best preparation, of course, is to avoid recalls altogether by following appropriate manufacturing quality regulations.
To avoid manufacturing-related defects in drugs, FDA regulations require that companies follow current good manufacturing practices (cGMPs). The FDA's recent emphasis on bringing greater control to manufacturing through the use of process analytical technology (PAT)—in-line and on-line analytical instrumentation with software to analyze data and effect control—and improving process understanding through Quality by Design—raises the bar even further for improving manufacturing quality.10
To avoid design flaws in medical devices, the applicable regulations are the "design control" sections in FDA's Quality System Regulation (21 CFR 820), and the international quality management standards ISO 9001 and ISO 13485. Design validation is required.
New medical devices that are part of drug–device combination products are increasingly dependent on software. The FDA is sensitive to the importance of software and is increasing its scrutiny of medical device software, requiring a system-level hazard analysis and software validation before granting clearance to market.
The allegations that Toyota's problem related to software problems highlight the importance of software validation and suggest that designing in manual overrides is recommended.
10. THE COMPANY, NOT THE FEDERAL AGENCY, IS RESPONSIBLE
Toyota example: In the case of the Toyota recall, the National Highway Traffic Safety Administration (NHTSA) came under criticism for not having seen the problem coming and for not doing more.
Lesson for Pharma: We should recognize that primary responsibility for the identification and prompt handling of field problems resides with the firm. It is easy to try to blame the regulatory agency, but the regulatory body is just a check on the system, not the responsible party. That is why the FDA allows a firm to make an expeditious change in warnings or precautions in product labeling by using the "Supplement—Changes Being Effected in 30 Days" provision.11
The challenge for the FDA is to keep up with rapidly changing technology. Frankly, the greater expertise resides in private industry.
11. KNOW AND OBEY THE RECORDKEEPING RULES
Toyota example: Toyota has been accused of withholding documents from plaintiff attorneys that reflect on safety. Toyota disagrees with those criticisms, because it considers documents related to engineering design to be proprietary and confidential.12
Lesson for Pharma: There are regulatory and legal requirements to maintain records for specified times and to make them available to regulatory authorities and for some court proceedings. Pharmaceutical companies must maintain records for 10 years of all adverse drug experiences known to the company, including raw data and any correspondence relating to adverse drug experiences.13 These raw data and correspondence include emails and even notes written on desk blotters. When you are putting something in writing, think through your statements carefully and avoid emotional language.
12. CONDUCT A GOOD RISK ANALYSIS
Toyota example: Could Toyota's recent quality problems have been avoided? The answer is "probably yes," if an effective risk analysis had been performed at the design stage, before large-scale manufacture.
Lesson for Pharma: FDA and ISO standards and guidelines call for risk analyses. In the lifecycle of a pharmaceutical device, the best opportunity to perform a risk analysis is at the design stage, before scale-up. One very useful tool is failure modes and effects analysis (FMEA). The FMEA technique incorporates a brainstorming session to uncover potential failures, which are then scored for severity, likelihood of occurrence, and whether there are any controls in place to detect a failure. The end result is a punch list of potential failures that require preventive actions to avoid later problems.
Future university graduate management programs will discuss the Toyota Recalls of 2009–2010 as a case study in what to do and what not to do when a technical malfunction results in a major recall. Lessons will be learned.
"We learn wisdom from failure much more than from success. We often discover what will do, by finding out what will not do; and probably he who never made a mistake never made a discovery." Samuel Smiles (1812–1904).
Robert N. Borghese is the president of Borghese & Associates, Whitehouse Station, NJ, 908.534.5354, firstname.lastname@example.org.
1. LaPonsie M. 2010 global Toyota recall. Autotechrepair.suite101.com. 2010 Feb 3 [cited 2010 April 3]. Available from: http://autotechrepair.suite101.com/article.cfm/2010-global-toyota-recall.
2. Maynard M. An apology from Toyota's leader. The New York Times. 2010 Feb 24 [cited 2010 April 3]. Available from: http://www.nytimes.com/2010/02/25/business/global/25toyota.html.
3. Woodyard C. Toyota CEO Akio Toyoda to House committee: Rapid growth to blame for safety lapses. USA Today. 2020 Feb 24 [cited 2010 April 3]. Available from: http://content.usatoday.com/communities/driveon/post/2010/02/my-name-is-on-every-car-ceo-akio-toyoda-will-say-toyota-grew-too-fast/1
4. Kubo N, Crawley J. Toyoda faces critical lawmakers over safety flaws. Reuters. 2010 Feb 24 [cited 2010 April 3]. Available from: http://www.reuters.com/assets/print?aid=USTRE61D2TS20100224
5. Deaths from runaway Toyotas put at 39 by investigators. ABC News /The Blotter from Brian Ross. 2010 Feb 24 [cited 3 April 2010]. Available from: http://abcnews.go.com/Blotter/RunawayToyotas/deaths-runaway-toyotas-put-39-investigators/story?id=9929661
6. Postmarketing reporting of adverse drug experiences, 21 CFR 314.80, and Postmarketing reporting of adverse experiences, 21 CFR 600.80.
7. Complaints continue after Toyotas are fixed. Associated Press (AP). 2010 March 4 [cited 3 April 2010]. Available from: http://abclocal.go.com/wabc/story?section=news/consumer/recalls&id=7309147
8. LaHood: Recalled Toyotas Not Safe. CBS News.com. 2010 Feb 24. [cited 3 April 2010]. Available from: http://www.cbsnews.com/stories/2010/02/24/business/main6238448.shtml
9. Enforcement policy-Firm-initiated recall, 21 CFR 7.46
10. US Food and Drug Administration. Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance. Rockville, MD; 2004 Sept. [cited 3 April 2010]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070305.pdf
11. Applications for FDA approval to market a new drug-Supplements and other changes to an approved application, 21 CFR 314.70.
12. Mitchell J, Searcey D. Toyota Accused of Withholding Records. The Wall Street Journal. 2010 Feb 27 [cited 3 April 2010]. Available from: http://online.wsj.com/article/SB10001424052748704625004575089803880464096.html
13. Postmarketing reporting of adverse drug experiences—Recordkeeping, 21 CFR 314.80(i).