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Agnes Shanley is senior editor of Pharmaceutical Technology.
Industry practice has changed radically over the past five decades. Can laws published in the 1960s still ensure pharmaceutical quality and safety today?
In the pharmaceutical industry, it often takes tragedy to lead to the passage of important laws. The Food, Drug, and Cosmetic (FD&C) Act of 1938, which established FDA’s authority over questions of drug safety in the United States, was passed after more than 100 people in 15 states died. The victims had ingested the first liquid form of sulfanilamide antibiotic, dissolved in a toxic-and at that point untested-solvent, diethylene glycol (1).
Current good manufacturing practices (cGMPs)-which set firm requirements for the safe manufacturing of finished drug products, and for plant and process design and operation-were passed in 1963 to update the FD&C Act. They came as a response to deaths caused by Winthrop Pharmaceutical’s failure to prevent cross-product batch contamination. The company had used two tableting machines within the same room, interchangeably, to manufacture antibiotic and anticonvulsant tablets. Lax controls led to the release of antibiotic tablets that had been contaminated by the anticonvulsant at two to three times the non-lethal dose; hundreds of people died or were hurt after taking the contaminated antibiotic (2–4).
Comprising the US 21 Code of Federal Regulations (CFR) Parts 210 and 211, and 212 for some radiopharmaceuticals, cGMPs aim to ensure that pharmaceutical processes and facilities are designed, monitored, and controlled properly, says Michael Kopcha, director of the Office of Pharmaceutical Quality (OPQ), at FDA’s Center for Drug Evaluation and Research (CDER). Unlike voluntary guidances and best practices, cGMPs are the law and must be followed by drug manufacturers. Recently, FDA has extended cGMPs into dietary supplements and compounding.
FDA last formally revised pharmaceutical cGMPs in 1977; since that time, the agency has published new guidance documents meant to improve manufacturers’ approaches to risk assessment and process understanding and control, with the 21st Century cGMPs (5) and process analytical technologies (6) guidances in 2004, and the revised process validation guidance (7) in 2011.
The industry has undergone radical changes, however, since 1977. Instead of focusing on large-volume “blockbuster” drug markets, pharmaceutical manufacturers now juggle larger product portfolios with smaller, globally diverse markets. In addition, they source most APIs from India and China, and outsource more strategic operations to contract research organizations (CROs) and contract development and manufacturing organizations (CDMOs).
At the same time, the industry has become far more complex with the growth of biopharmaceuticals, the shift from branded to generic pharmaceuticals, and the move to biosimilars and personalized medicine. “When cGMP came into effect, pharma companies were vertically integrated,” says Hedley Rees, managing consultant of PharmaFlow Ltd., based in the United Kingdom. “Quality systems were under the ownership of the companies developing and manufacturing the products, with a shared set of standard operating procedures and business objectives. The people working in the pharma companies all had skin in the game; they shared the pain and the rewards in the journey to regulatory approval,” he adds. The past four decades have seen supply chain complexity increase by an order of magnitude, Rees says.
Should cGMPs be revisited and updated, given the fundamental changes that have taken place within the industry since they were published? Opinion on the subject is divided. At this point, FDA has no plans for any major revisions of US cGMPs. “We intend to continue modernizing or clarifying the regulations as needed to harmonize them with other FDA regulations and international cGMP standards, and to use guidance for industry as a primary way of developing and explaining our recommendations for complying with the statute and regulations,” says FDA’s OPQ Director Kopcha.
However, some within the industry believe that cGMPs need an overhaul. “The current CGMP regulations clearly need updating to reflect the current state of complexity in pharmaceuticals materials, processes, products, and supply chain,” says Ajaz Hussain, consultant, head of the National Institute of Pharmaceutical Technology and Education (NIPTE), and formerly head of FDA’s Office of Pharmaceutical Sciences at CDER.
“FDA’s periodic updates have been a bit like patches on software or add-ons to an existing building. It may take years, but cGMPs need to be modernized,” says consultant Emil Ciurczak, an early adopter of process analytical technology (PAT) and president of DoraMax Consultants.
The task would be herculean, notes Hussain. “We have done all that we can to avoid having to do the update, with guidelines and guidances. That has been the entire basis of the 21st century initiative,” he says.
One challenge is that FDA’s guidance documents, whether on PAT or process validation, only present suggestions and companies can-and often do-bypass them, as long as they meet legal product quality requirements. Some observers ask whether some suggested practices might need to become required ones if the industry is to develop a more scientific approach to manufacturing and quality control.
Industry observers pinpoint the need for more cGMP clarity in:
Hussain believes that US 21 CFR 211 Part 11 Subpart B, which covers requirements for organization and personnel, should be a high priority target for cGMP clarification and updates. He points to recent FDA warning letters that refer to CFR 211, specifying deficiencies in production record review, batch record and maintenance data practices, training, and investigation of batch failures or other discrepancies.
Even though regulators may not explicitly refer to Subpart B in their citations, Hussain suggests, companies’ failure to follow its requirements is often the root cause of many, if not most of the cGMP problems that regulators do cite.
“The cGMPs drafted in 1977 had called for adequate education, training, and experience. But when have we ever defined what ‘adequate’ means for people who work in cGMP, for the inspectors at FDA, for the reviewers at FDA? We have this fundamental flaw in the system,” Hussain says. “So how can we expect people who are not qualified for their jobs to do anything better? “Our attention needs to be focused on being objective,” he adds. Hussain sees professional development as the key to developing the type of managers needed to instill a “culture of quality” within the industry.
Inadequate management training and development may also have implications for the industry’s use of technology, says consultant Gary Ritchie. He uses digital records as an example. Like paper-based records, digital records are subject to the predicate rule; they must be retained for a set period of time after the drug expires. But digital records offer an immediate transparency that paper does not. “In some cases, companies are afraid to be stuck with electronic records that actually show how management made decisions when they processed something. You cannot erase the record,” he notes.
“The reality is that people are still working on paper in the 21st century digital world, because it is more flexible,” says Ritchie. “FDA has suggested that, in the future, it may not allow hybrid (i.e., paper-on-glass) systems, but until the science of manufacturing evolves, change won’t take place,” he says. “FDA wants to hold up as an example those companies that have moved to digital records, but there are still so many more facilities that use paper and whose practices remain stuck in the 1900s.”
Another area where cGMPs could be shored up, observers say, is in process validation and delineating the expectation of statistically valid sampling and statistical process control. “That was the stated principle behind FDA’s process validation guidance in 2011,” says Hussain. As he notes, only a handful of Big Pharma companies appear to be using modern process validation principles correctly. “The rest are struggling, and haven’t even begun to use the concept for new, let alone legacy, products,” he says.
One problem pointed out by FDA compliance officer Grace McNally in a 2011 presentation is a failure to use the best statistical methods and validation principles. As she noted, “At times, compendial standards take on the character of statistical procedures … but, in all cases, statements about whether the compendial standard is met apply only to the units being tested” (8). Optimal production calls for meaningful in-process tests and for a statistically significant number of tests based on batch size of final dosage forms, Ciurczak says; companies may be following traditional practices, yet failing to meet the requirements set by cGMPs. “Let’s say that a company tests 20 tablets out of two million. Even someone without a math background knows that’s not statistically significant,” Ciurczak says. He uses military standards as a contrasting example. “If you are manufacturing more than a half million units, the US Department of Defense says that you must run 25,000 tests. If a pharma company had to run 25,000 HPLC [high-performance liquid chromatography] tests, it would cost way too much and it wouldn’t show what was happening in the other 1.75 million.” Finally, there are the tests themselves, and whether they make sense given today’s manufacturing realities. “Friability and disintegration tests are not meaningful, and they are simply not timely anymore,” says Ciurczak. “They may have been timely when you had a single-punch machine that was putting out 100 tablets an hour. They are not timely when you have a 36- or 40-punch machine that is putting out 100,000 or 200,000 tablets an hour,” he says.
FDA’s 2011 process validation guidance was supposed to mean the end of the “three batch” rule for product release but that concept is still alive and well at many companies, and sampling is still being handled in a rather primitive way at some facilities, says Ciurczak.
The problem with adherence to this practice is the fact that “any time you take selective samples, you’re guessing,” Ciurczak explains. If one could place hidden cameras in many oral solid-dosage form facilities today, he says, one might often see operators taking material from the top of the last drum, scooping it out and calling it representative of the entire last batch, instead of sampling every drum at different levels using different sample thieves.
One obvious solution would be to use PAT, but many manufacturers still aren’t, Ciurczak says. “With PAT, you have in-process tests and the potential of 100% analysis. There are online options that can automatically examine 100,000 tablets an hour, and there is zero excuse for not using them.” Ciurczak also sees a need for cGMPs to specify better calibration methods. “GMPs are based on 1950s technology, and they don’t stress raw material quality enough,” he says, at a time when most materials are being sourced from regions where regulatory practices are still evolving. For instance, cGMP practice still accepts the use of compendial testing, even though some older United States Pharmacopeia (USP) tests have proven to be fallible, as was seen during the heparin recall of 2007. “Spot and color tests for heavy metals might have been okay when pharmacists were making things in their back rooms and selling them locally, but now you’re sourcing materials from halfway across the world and the identity tests won’t show whether they are even useable,” says Ciurczak.
The biggest problem with cGMPs, Ciurczak says, is that they are “one size fits all.” FDA, however, cannot mandate the approaches that companies use to meet requirements. “Measurements, process release, and in-process measurements are not mandatory. PAT methods may reduce variability in commercial product, but how the manufacturer achieves required targets is up to them,” says Ritchie. However, he notes, when something tragic happens, it’s usually lawyers who point out that management knew that other options were available but chose not to use them. This may prove to be grounds for future liability and accusations of negligence, he suggests.
Some believe the problem is much bigger than cGMPs alone, and requires that drug development and manufacturing, and the chemistry, manufacturing, and controls, and manufacturing functions become more closely connected. “Drug development must undergo wholesale change as product development did in other exemplary companies in other industries in the 1960s,” says Rees. “These companies placed the end user of their products at the center and developed a value chain to deliver on their needs in terms of value for money. They achieved incredible improvements in quality by placing the responsibility for defects on the production operators, rather than a ‘quality function.’ The production operators were given the tools of statistical process control and they used them to great effect, achieving six-sigma quality levels (i.e., 3.4 defects per million opportunities),” he says. Amgen is one of a few biopharmaceutical and pharmaceutical manufacturers that has achieved this level of quality.
At the same time, Rees explains, forward-thinking manufacturers in other industries began to design for manufacture, as opposed to throwing processes “over the wall.” They adopted a collaborative approach, he says, in which design and production departments worked together to achieve the crucial balance between innovation and production feasibility and economics. “The results were transformational,” says Rees, who has commented on some of these issues in his new book, Taming the Big Pharma Monster, published in May 2019 (9). Rees sees the answer as going back to a simpler time, and to vertical integration. But one might ask: How can decades of industry change be reversed? For now, it remains to be seen if and how regulators will address the need to clarify industry’s interpretation of cGMPs. Hussain suggests breaking the problem down into smaller bites. “The cGMPs for nutritional supplements, compounding, and tobacco are still evolving. Perhaps the first order of business is to bring some sanity to the definition of adequate education, training, and experience, since the entire system rests on this foundation,” he says.
1. C. Ballentine, “Sulfanilamide Disaster,” FDA Consumer Magazine (June 1981) .
2. JP Swann, Pharm Hist. 41(1) 16-25 (1999).
3. R. Pepling, Chemical & Engineering News 83 (25), (June 20, 2005).
4. K. Stone, Current Good Manufacturing Practices, thebalance.com, March 7, 2019.
5. FDA, Pharmaceutical cGMPS for the Twenty-First Century: A Risk-Based Approach, Report (September 2004).
6. FDA, Guidance for Industry, PAT-A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, (Rockville, MD, September 2004).
7. FDA, Guidance for Industry, Process Validation: General Principles and Practices (Rockville, MD, January 2011).
8. G. McNally, “A Practical Approach to Effective Life Cycle Implementation of Systems and Processes for Pharmaceutical Manufacturing,” presentation at the Pharmaceutical Quality Systems (ICH Q10) Conference, Arlington, VA, Oct. 4–6, 2011.
9. H. Rees, Taming the Big Pharma Monster, Filament Publishing; (May 13, 2019).
Vol. 43, No. 7
When referring to this article, please cite it as A. Shanley, “Is it Time to Update cGMPs?" Pharmaceutical Technology 43 (7) 2019.