				What are current good manufacturing practices (cGMPs)? Where did they come from? What are the actual "practices" described in the Code of Federal Regulations, 21 CFR. If you are new to the pharmaceutical or biotechnology industries, you may enter your first "GMP Training" session without much context or perspective. A set of arcane rules is presented; you were never taught these in science classes. What is all the fuss about? The emphasis makes you think it is difficult, but the content may seem quite simple... until you go and try to put them into practice. 

The GMPs are federal regulations that have evolved over the last century, in response to a series of public health disasters. Different sections of the law apply to different industries; this article is concerned with those that apply to drugs, medical devices, and biological pharmaceuticals. 			

What these products have in common is that they are highly complex and have stringent quality requirements. The consequences of using a product that does not meet its quality attributes can be fatal. Unlike other products, consumers are unable to check the quality before they take a pill. Therefore, the government has stepped in to set minimal standards and define the systems and processes that must be in place to provide reasonable assurance of quality. The GMP regulations define those systems with enough ambiguity to permit each firm to construct its own processes that will meet the requirements. FDA is the US agency responsible for enforcing the regulations. 

What is codified in the GMPs? They represent an array of tactics that seek to reduce the probability of harm to the end user of a drug, device, or biological product. Although the risks cannot be reduced to zero, following GMP guidelines greatly reduces risk. Canada, Europe, Japan, and other countries all have similar rules, and any manufacturer must comply with these rules in order to sell its products. 			

Unlike other products, many of a drug's quality attributes cannot be detected by the consumer. The consumer must be able to trust the quality of the medicine over time and over different production lots. To achieve this, FDA acts as a regulator and formulator of standards, defining an acceptable level of risk. This acceptable risk varies with the patient population, the disease being treated, and the values of our culture. For example, we accept more risk for a late-stage terminal patient receiving last-effort treatment than for a healthy baby about to receive a vaccine. However, we require that all medicines used in humans meet a high standard of safety and consistency. 

Let's look at some of the key events that led to establishment of some of the GMP rules. 

Vaccine Events — Diphtheria, Tetanus, and Others

GMP rules are easier to understand after you realize they are responses to actual historical events. Vaccines were developed empirically, and the critical parameters that assured efficacy and safety were not well understood initially. As a result, the main approach to safety assurance was change control: "The process defines the product." Any change might make the vaccine unsafe, and extensive testing and an application process were necessary to gain approval. 			

The source of this thinking can be traced back to 1901, when children who received antitoxin for diphtheria treatment died of tetanus. The horse serum that had been used to prepare the antitoxin was contaminated with tetanus. Thus, the importance of high-quality raw materials was graphically demonstrated, along with the ability of animal-derived materials to pass diseases both known and unknown. 

The Biologics Control Act was passed in 1902, to improve the assurance of safety and purity of sera, vaccines, and other biological products. The Food and Drugs Act was first passed and put into law in 1906 and revised as the Food, Drug and Cosmetic Act of 1938. The original law focused on misbranding and adulteration of foods, drinks, and drugs, and only restricted interstate commerce. At the time, the main target was patent medicines and foods that often contained toxic ingredients and made unsupported claims of effectiveness. The 1938 revision extended control to cosmetics and therapeutic devices, required that a new drug be shown to be safe, authorized factory inspections, and required that specifications be set for any unavoidable poisonous substances in drugs. 

In 1937, thousands of people were exposed to toxic cough syrup, and 107 people died. The culprit was diethylene glycol, which had been used in lieu of the safer propylene glycol. A lack of control and standards for choosing ingredients that were low in toxicity was the root cause of this and other, similar events.   			

Both deliberate and accidental use of inappropriate raw materials has been documented. For example, jake leg, a neurological disease found in consumers of moonshine whiskey, resulted from addition of an ingredient thought to be safe. Other errors have occurred when unsuitable raw materials were used by accident. Identity mix-ups continue to be a leading cause of medical errors today. Items with similar names, packaging, or labels are easily confused with each other. Many sections of the GMP regulations seek to assure that different medicines are easily distinguishable from each other, that labels are legible, and that they contain all the relevant information. 

Resulting regulations include 21CFR 211: 184, which requires that the identity of each shipment of each raw material be confirmed before it is put into use; requirements that tablets and capsules have distinctive shapes and colors and sizes that permit them to be easily distinguished by appearance; and requirements to check and double-check labels during risky operations where mix-ups are more likely to occur. For example, detailed requirements are explicitly stated in the GMP regulations for weighing raw materials and packaging drug products. 

			Insulin, a life saving treatment for diabetics, demonstrated the importance of controlling and accurately measuring potency, which is the ability of the drug to exert its biological effect. The dosing of insulin must be tightly controlled because both too-high and too-low levels can be life threatening. Variation in insulin potencies between product lots caused many safety events and led to the Insulin Amendment of 1941. For the first time, this required that both the manufacturer and FDA test and release drug product on a per-lot basis for purity and potency. The federal laboratory thus vetted the quality control laboratory within the firm and served as an additional checkpoint. This requirement was extended to many other biological products and phased out only after an extensive track record of consistency was established. Today, we also see the effects of the insulin experience in the rigor with which analytical release methods must be validated for linearity, selectivity, accuracy, robustness, and precision. 			

			In the Cutter incident of 1955, two polio vaccine lots resulted in at least 250 cases of polio. The vaccine, supposedly inactivated, still contained active virus for unknown reasons. Certain lots of other vaccines, including those for yellow fever and rabies, also gave the recipients the disease instead of protecting them from it. In some cases, these incidents were traced to process changes or variances that were believed to be insignificant but actually resulted in incomplete virus inactivation. 			

These and other events marked the emergence of strict process validation. Ranges must be defined within which the process has a high probability of yielding a product that meets its specifications. The 1987 Guidelines for Process Validation are currently in revision. Numerous guidance documents, including FDA "Points to Consider" and International Conference on Harmonization guidelines have addressed the special issues of virological safety and methodologies for evaluating processes for freedom from adventitious agents. The Division of Biologics Control was created within NIH to oversee vaccine safety. Today this is the Center for Biologics Evaluation and Research (CBER), now part of FDA. 

The 1972 Devonport, UK, incident resulted in at least five deaths when drug products designed to be sterile became contaminated and recipients developed infections. An unwritten change to autoclave operation, communicated orally between operators, resulted in dextrose IV solutions that were not uniformly sterile. The Clothier inquiry, which examined the causes and contributing factors, identified several violations of what we now consider basic GMP. 							

The chain of events that compromised the safety of the drug products included inadequate maintenance, inadequate understanding of autoclave operation, and regular deviations from the written production instructions (often attempting to compensate for equipment malfunction). Together, these factors resulted in a sterilization cycle that did not assure that all vials in the autoclave were sterilized; thus, some doses were safe while others led to sepsis in patients who received them. This incident helped to define sterility assurance in an operational way. Processes and requirements for equipment validation were created, and the legal right of inspection was explicitly given to the agency. 

Validation was developed as a means of documenting systematic evaluation of the sterilization cycle — building in a safety factor — and identifying the critical parameters that need to be controlled to assure process performance. The concept that quality must be designed into the process and cannot be achieved only by testing remains a central tenet of cGMP. In other words, how you make something helps to define its level of quality. Preventing errors is more effective than finding rejects because it is not possible to detect all rejects. 

One of the saddest events in the pharmaceutical industry occurred in the early 1960s. Thalidomide, prescribed for sleep problems, was shown to be safe in clinical trials in healthy adults and was subsequently prescribed to patients, including pregnant women, in Europe. Although safe in adults, thalidomide was toxic to fetuses, and thousands of victims were born with major birth defects. Because FDA hesitated to approve thalidomide, its impact in the US was much less severe than in Europe. 			

This incident demonstrated that the choice of subjects in pre-clinical and clinical trials is critically important for evaluating safety. Regulations now require reproductive studies in two or three species of animals prior to human clinical trials; newer requirements also require the consideration of gender, race, age, and other characteristics in the design of clinical trials. The data have shown that not only safety, but also efficacy, can vary among sub-populations, and are shedding new light on genetic differences between individuals. In reaction to the thalidomide epidemic, the US Congress passed the Kefauver-Harris Drug Amendments, which required that a manufacturer prove effectiveness as well as safety before marketing products. 

In 1982, several consumers of over-the-counter Tylenol capsules suddenly died of cyanide poisoning. An intensive investigation of the production records showed that this was not the result of a raw materials mix-up during manufacturing. Rather, tampering apparently occurred on store shelves. A new vulnerability was identified in the supply chain. 			

The manufacturer, Johnson and Johnson, notified the public and voluntarily recalled its entire product in what is now a textbook case of how to respond to a health disaster. Their development scientists went into overdrive to re-design the capsule to make tampering more difficult and more detectable. The industry as a whole re-evaluated the means of delivering over-the-counter medicines. Regulations were updated starting in 1982, and they now require tamper-resistant packaging that aids in the detection of tampering. Without these steps, over-the-counter pharmaceuticals could have become an unacceptable safety risk. 

			In 1989, an outbreak of toxic reactions to over-the-counter L-tryptophan, a dietary supplement, resulted in 38 deaths and probably thousands of less severe reactions. The event was the result of a manufacturing process change that increased the level of a harmful byproduct. Doses that had previously been safe now caused toxicity. One response to this event was the clarification of requirements for characterizing drug impurities and new requirements for evaluation of minor impurities. In the biological products area, extensive policy and guidances have been issued on how to establish comparability when process, facility, or other changes are made. 			

The most basic section of the GMP regulations, 21 CFR 211:80, can be paraphrased to state, "Thou shalt have written procedures, and thou shalt follow them." This remains the most-cited violation of the GMPs — not because it is difficult to understand but because it is such a challenge to comply. The consistency of any product results from the ability to repeat the procedures faithfully over a long period of time, despite changes in equipment, staffing, and other factors. Batch record review, performed by a quality assurance group, is one means of checking the fidelity with which the recipes are followed. Training programs seek to prevent inconsistencies from occurring and should be repeated periodically to reinforce the importance of following procedure exactly as written. The GMP regulations spell out basic qualifications and training requirements for all individuals engaged in GMP functions, including consultants. 							

The GMPs specify that the quality control unit must have organizational independence from manufacturing — with sole authority to release or reject product, raw materials, key procedures, specifications, and reports. Why go to such great lengths, and surely add to the cost of medicines, in this way? The answer, again, lies in human nature and experience. Production personnel are focused on delivering product on time. If asked to judge the quality of the product they have just produced, they face a conflict of interest. To assure safety for the consumer, an internal group must be insulated from supply chain pressures and given a different priority: quality. The quality unit provides systems, interprets regulations, and sets the philosophy within the firm. It is the judge when GMP decisions must be made and is held responsible, along with executive management, for product quality. The regulations make it clear that QC oversees production and assures that procedures are being followed. The ability of quality assurance to reject or recall bad product is the last safety check that keeps the consumer from harm.   

Table I lists the key stipulations of the GMP regulations. The regulations specify basic, minimum requirements for the buildings and facilities in which pharmaceuticals are manufactured, stored, or handled. These emphasize prevention of contamination or cross-contamination, adequate labeling, and building design to prevent mix-ups. These also cover standards for the quality of the air, production surfaces, and gowning in controlled areas to maintain a clean safe environment.  			

Subpart F of 21 CFR 211 discusses production and process controls, defining the systems required to maintain a "state of control." A large section is devoted to control of raw materials and components, perhaps because so many tragic events resulted from the use of improper or contaminated materials. 

You may wonder why the packaging and labeling section is so detailed. Even today, with the benefit of over a century of regulation in the industry, mix-ups and labeling errors still remain the number one sources of adverse events in hospitals as well as homes. The risk of mis-labeling a drug product is reduced by having dedicated, segregated areas; by controlling the labels; by instituting multiple line checks; and by performing reconciliation. Reconciliation is the process of comparing counts of labels or other items before and after a process step, in order to check for strays. The process of reconciliation has prevented numerous potential medical accidents from occurring. The discovery that 25 kgs have been removed from a 10 kg container can greatly aid in discovering that a mix-up has occurred. 

			Today, more people than ever are taking pharmaceuticals. Adverse events do happen, and some lots of product that have met specifications are released to the public, and are later recalled due to quality concerns. However, the incidence of safety problems is quite low as a result of GMP systems, talented people, and the use of advanced technologies. 			

As with democracy, the GMPs work quite well but not perfectly. The quality of a medicine depends on every individual person, instrument, and material in the production chain following defined systems and processes. Quality systems are the back-up that help to assure that errors will be detected and impact assessed before the product is released to the public. Most adverse events can be traced to a violation of one or more of the GMP rules, suggesting that GMP is a powerful way to assure quality. Until someone comes up with a better way, GMPs are likely to remain with us.  

1.  FDA. 21 CFR 210, 211, 800. Available at: 

2.  FDA. Milestones in US food and drug law history. Available at 

www.fda.gov/opacom/backgrounders/miles.html

3.  Young JH. Sulfanilamide and diethylene glycol. In Parascandola and Whorton, editors. Chemistry and modern society: historical essays in honor of Aaron J. Ihde. Washington, DC: ACS; 1983.

Paula J. Shadle, Ph.D., is the principal consultant at Shadle Consulting, 501 McBride Drive, Lafayette, CA  94549, 925.878.5130, fax 925.962.0862, 

Articles

Overview

What are current good manufacturing practices (cGMPs)? Where did they come from? What are the actual "practices" described in the Code of Federal Regulations, 21 CFR. If you are new to the pharmaceutical or biotechnology industries, you may enter your first "GMP Training" session without much context or perspective. A set of arcane rules is presented; you were never taught these in science classes.

Overview of GMPs

				Good manufacturing practices (GMPs) are manufacturing guidelines for ensuring the safety and efficacy of drug products and medical devices. The GMPs are legal regulations, based on the United States Food, Drug and Cosmetic Act. But, why do we need the GMPs? Shouldn't we, as knowledgeable individuals, groups, and companies, be able to figure out how to produce drugs and devices that are safe and effective?

The answer is "yes and no." We are knowledgeable, but we do need our work to be guided by stated expectations. All aspects of a complex society require rules. Why should our industry be any different? After all, these products can be life-saving or, if impure, a serious health threat. Even lawnmower manufacturers and bridge builders are adopting standardized manufacturing rules. 

The GMPs are promulgated by FDA. However, FDA is part of the U.S. Public Health Service (USPHS). Ensuring the safety of drinking water is a good example of USPHS's role. Water can be an efficient means of transmitting diseases, such as cholera, cryptosporidium, and enteroviruses. USPHS's approach prevents illness by protecting water sources and minimizing the risk of disease through filtration and disinfection. Likewise, FDA is entrusted with ensuring public health — preventing harm to the public from drugs and medical devices. The agency also is charged with ensuring products are efficacious. These are consequences of a public health approach: FDA oversees proactive measures to ensure these objectives are routinely met, which is where GMPs fit in. 

		If you look at the manufacturing systems of three different pharmaceutical companies, you will likely find three different sets of terminology, procedures, and activities designed to ensure compliance with GMPs. How can this be, if all three are following the GMPs? 			

The answer is easy: the GMPs are not checklists. They do not describe how work is to be performed; they define the required outcome of the work performed. How an organization chooses to achieve these outcomes is determined by that organization. 

For example, the GMPs do not state that a documentation system is required; however, the phrase "written procedures shall be established and followed for..." is used throughout the GMP regulations. If a documentation system is not in place, how else can the required outcome, specifically that written procedures be established and followed, be achieved? 

Despite what some critics of the GMPs have stated, they are flexible. They require manufacturers to evaluate the outcome articulated in the regulation, assess how that outcome can best be achieved, and then implement it. Finally, they must ensure that compliance with GMPs can be demonstrated — for example, to FDA inspectors and collaborators.  

cGMP stands for current good manufacturing practices. One heavily debated issue in GMP discussions is to "c" or not to "c". Does GMP = cGMP? Yes.  

FDA expects organizations to take the appropriate steps to ensure that the safety, identity, strength, quality, and purity of a drug product is preserved. The scope of GMPs is stated in 21 CFR 211.1(a): "The regulations in this part contain the minimum current good manufacturing practice for preparation of drug products for administration to humans or animals." Also, note the word minimum.  

GMP implementation never stops, as the GMPs continue to evolve. The stimulus for revision comes from a variety of areas, including FDA observations made during site inspections. Many years ago, as the story goes, an inspector discovered that a manufacturing plant's toilet facilities consisted of an outhouse outside the plant (remember that GMPs came into existence in 1978). The rule addressing this topic now reads as follows: 					

Sec. 211.52  Washing and toilet facilities.

 Adequate washing facilities shall be provided, including hot and cold water, soap or detergent, air driers or single-service towels, and clean toilet facilities easily accessible to working areas.

As another example, the GMPs did not always say that written procedures were necessary and compulsory. Some enterprising individuals argued that because the regulations did not require that their written procedures be followed, they didn't have to do so. The phrase, "written procedures shall be established and followed for...," now appears in the GMPs at least 100 times. 

Implementing revised GMPs can be equally tricky for a newly established organization or one that has been in business for many years. One of the biggest issues is interpreting exactly what the desired outcome of the regulation is. Once that hurdle has been overcome, the next is assessing whether practices to ensure this outcome are already in place. If so, there is no problem. If not, then integrating new practices into an existing way of doing work can be challenging. Rewriting procedures and re-training personnel takes time.  

One of the most important ways of reducing implementation challenges is keeping it simple. Making it easy for personnel to comply with internal organizational requirements reduces the risk of an FDA observation reading, "Internal procedures were not followed." Maintaining perspective on the big picture — GMPs define outcomes — will facilitate understanding and long-term compliance with GMPs. 

Janet Rose Christensen is vice president, regulatory affairs and quality, AVI BioPharma, One SW Columbia Street, Suite 1105, Portland, OR 97258, 503.227.0554, 

Why GMPs

Good manufacturing practices (GMPs) are manufacturing guidelines for ensuring the safety and efficacy of drug products and medical devices. The GMPs are legal regulations, based on the United States Food, Drug and Cosmetic Act. But, why do we need the GMPs? Shouldn't we, as knowledgeable individuals, groups, and companies, be able to figure out how to produce drugs and devices that are safe and effective?

Why GMPs? What are GMPs and Why Do We Need Them?

				GMP is the acronym for Good Manufacturing Practice. The GMPs represent a set of regulations that were promulgated as a final rule by FDA in 1978 and intended to ensure the safety and efficacy of the nation's drug products. The GMPs, as we know them today, are the result of over a century of actions by industry and reactions by government and consumer groups to bring guidance and controls to the food and drug industry, resulting in a safe supply of food and medicines. GMP compliance is the foundation of the pharmaceutical industry and has become the benchmark for success of any enterprise involved in the development, manufacture or testing of human and animal drug products. Often, the prefix c is used to indicate cGMPs. The c stands for current and raises regulatory expectations beyond the stated regulations to include current, state-of-the-industry standards.  

Without robust quality systems supporting the manufacture, testing, and distribution of pharmaceuticals, our society, as we know it could not survive. When patients use medicines, they do so with the implicit knowledge that entire organizations went to painstaking efforts and extremes to ensure that the drugs are of the utmost quality. The GMP regulations far surpass the Hippocratic oath's requirement to "First Do No Harm," by requiring process and laboratory controls, verification and approvals, quality controls, structure and organization, material management, validation, and accurate documentation of these and other requirements. These controls are intended to ensure safe, pure and efficacious medicines are produced and available to patients in need.  

Besides patients, hundreds of thousands of government and private sector employees depend on the pharmaceutical manufacturing industry for their jobs and careers. Shareholders expect regulatory compliance to protect their investment. Countries depend upon the industry for the health of their citizens. Companies that cannot meet GMP requirements routinely suffer severe financial penalties in fines, lost revenue, and damage to their reputations. 

Industry personnel and government regulators involved in the research, production, and regulation of pharmaceutical products constitute society's most talented, dedicated workforce, devoted to their cause of helping mankind through the discovery and manufacture of medicines that cure and mitigate disease. The pharmaceutical industry is an intense, stringent, and competitive industry by nature. It is currently under extreme social and political pressure to deliver new medicines faster and cheaper. Existing regulations are being interpreted more conservatively and penalties for noncompliance — even for small errors — are at their highest in history. 			

People are not perfect, including the people who conduct the clinical studies, write the dossiers for submission and approval, obtain materials, and manufacture and package the medicines we consume. Good intentions can succumb to honest error, speed-to-market can lead to taking risky short cuts, and ambiguous data can be interpreted as acceptable. Regulations are necessary to provide a minimal guideline for ethics and acceptability. Without the GMPs, we would have chaos, and there would be no system to assess medicines. 

Enforcement of the GMPs is essential. FDA currently assesses acceptability of a drug product through its application review and facility inspection process. Reviewers at various centers evaluate scientific merit and supporting evidence, and field investigators perform onsite investigations to assure the information submitted in the application is authentic. Field investigators also perform an evaluation of the manufacturing environment, equipment, controls, procedures, and personnel. All of this is accomplished, in large part, by reviewing required documentation. 			

The number of domestic establishments FDA is required to regulate exceeds 120,000. Annual imports to the US number nearly 8 million shipments of FDA-regulated products from about 500,000 foreign manufacturers. Many of these foreign facilities have never received an FDA inspection.

 The agency is also being ordered by Congress to address even more complex issues, including bioterrorism, mad cow disease, foreign pharmacy imports, counterfeiting, and product diversion and tampering. Domestic and international regulatory agencies and customer expectations continue to demand increased compliance and consistent quality. 

Most standards are well written and understood, but many are not and have been subject to multiple interpretations not only by industry but also by FDA itself. 

Until recently, more than 25 years had passed since the last major changes were made to FDA's regulatory systems. Cognizant of new challenges facing both industry and the agency, FDA has initiated several new programs.  			

"Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach" was announced on August 21, 2002. This new initiative is intended to commence "a systematic reappraisal of FDA's approaches to product quality regulations." FDA's current inspection program is overburdened with new obligations and an increasing number of firms requiring inspection, while the number of completed inspections has been decreasing over the past several years.

FDA hopes to incorporate the most up-to-date concepts of risk management and use its resources effectively and efficiently to address the most significant public health risks, including: 			

encouraging the early adoption of new technological advances by the pharmaceutical industry

 facilitating modern quality management techniques, including implementation of quality systems approaches to all aspects of pharmaceutical production and quality assurance

 encouraging risk-based approaches that focus both industry and agency attention on critical areas

ensuring that regulatory review and inspection policies are based on state-of-the-art pharmaceutical science

enhancing the consistency and coordination of FDA's drug quality regulatory programs, in part by integrating enhanced quality systems approaches into the agency's business processes and regulatory policies concerning review and inspection activities.

As a result of the initiative, multidisciplinary working groups are developing guidance documents in various phases of completion. These documents are available on the agency's website (

Part 11, Electronic Records, Electronic Signatures — Scope and Application

Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical cGMP

Sterile Drug Products Produced by Aseptic Processing: Current Good Manufacturing Practices

Comparability Protocols — Protein Drug Products and Biological Products, Chemistry, Manufacturing, and Controls Information

PAT — A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance

FDA is also making important changes to its inspection program, including: 			

 The Office of Regulatory Affairs (ORA) and the Center for Drug Evaluation and Research (CDER) signed a memorandum of understanding establishing a Pharmaceutical Inspectorate (PI) within ORA. This PI will be staffed with highly trained individuals within ORA who will devote most of their time to conducting human drug quality inspections and other complex or high-risk pharmaceutical operations.

 To serve as a member of the PI, an investigator will have to obtain and maintain a Level III Drug Certification. This certification signifies that an individual has received extensive training on advanced technology in the pharmaceutical manufacturing process and how those technologies are evaluated during an inspection.

 A board has been established to review certification packages; select candidates for membership into the PI; and develop, update, and maintain the curriculum for the Level III Drug Certification program.  

 The pre-approval inspection compliance program has been revised, giving field offices more opportunity to utilize a risk-based approach in determining the necessity of pre-approval inspections.  

 The agency is emphasizing a risk-based approach in selecting inspection sites to ensure its limited resources are appropriately utilized. 

FDA is looking internally at quality systems and controls to enhance the consistency and predictability of their internal inspection program. The key message FDA wants to deliver is that "FDA is regulating product quality to serve the patient, and drug companies should view the patient as a customer, too." In the past, a lack of knowledge of what affected product quality led to FDA micromanagement of the inspection processes. FDA is adopting a more scientific and systems-based approach. If processes are well understood and controlled, FDA will be able to redefine their inspection approach. 

The agency also is conferring with private corporations, universities, and independent consultant groups to improve the way it manages its responsibilities. It is clear FDA believes there is no alternative but to continue in this direction.

Certain challenges face both FDA and the biopharmaceutical industry. Policy, regulation, and procedures must be known and practiced consistently so that industry can align practices with FDA expectations. The demands on manufacturers and regulators are increasing to the point where the system must change if it is to continue to function.  			

Future challenges facing pharmaceutical manufacturing organizations include:  			

Industry needs to stand its ground on scientific issues. The new initiative asserts that the regulatory process should be about science and an open exchange of views in order to assess product quality. FDA's new dispute resolution process also is directed at promoting and supporting such an approach. 

In September 2004, FDA issued the final report on its "Pharmaceutical GMPs for the 21st Century" initiative. The report addresses the outcomes of the original program and some additional efforts, in varying degrees of completion, that will become ongoing programs. Of significant interest, FDA formed the Council on Pharmaceutical Quality, which has been charged with policy development, coordination, and continuing change management, including the ongoing implementation of specific quality management systems within FDA's operations.   

Additionally, FDA issued a draft guidance titled 

Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations.

 Although this document is neither intended to create expectations for pharmaceutical manufacturers beyond current regulations or requirements, nor is it intended to be a guide for inspections, it will have a significant effect on future regulatory inspectional expectations and outcomes. The entire report is available at 

, both internal to the agency and as they apply to industry. What are quality systems and how are they used? Depending on whom you ask, you will receive a different response. The World Health Organization (WHO), International Conference on Harmonization (ICH), and American Society for Quality (ASQ) all differ on the topic to some degree. Even within individual companies, the definition often varies and the interpretation and use are unclear. However, one thing is clear: industry is empowered — and required — to define appropriate quality systems.  			

FDA has provided its definition of quality system within the draft guidance referenced above. It reads: "Quality System — formalized business practices that define management responsibilities for organization structure, processes, procedures and resources needed to fulfill product/service requirements, customer satisfaction, and continual improvement. In the cGMP regulatory context, the quality system establishes the foundation to promote the effective functioning of the five other major systems."

 FDA also states that the overarching philosophy in both the cGMP regulations and in robust modern quality systems is that quality should be built into the product, and testing alone cannot be relied on to ensure product quality. The guidance document goes into detail on acceptable models for quality systems and states that the cGMP regulations are inherently flexible to enable manufacturers to implement a quality system in a form that is appropriate for their specific operations. 

Defining quality systems requires careful thought and consideration. Quality systems need nurturing and support as they evolve. Every enterprise should have a quality manual that outlines its philosophy and expectations. Subordinate to that, standards and procedures that outline the execution and expectation of the quality philosophy and requirements are needed. Those procedures yield data and metrics that management must review for acceptability and corrective action. This structure, including all the operational specific systems required to ensure product quality, should constitute an enterprise's quality system. 

One useful way of defining quality systems is to say that they cover all the business-process systems that can, in any way, affect product quality or compliance. For example: raw material ordering and qualification, pest control, manufacturing, packaging and labeling, and others. Within this broad definition of quality systems it is important to identify the subset of processes formally owned by and the responsibility of the Quality Assurance Unit, for example: complaint reviews, product review, disposition, audits, and change control. Within the overall quality systems, these constitute the Quality System itself. 

System-based inspections (SBIs) are risk-based, shifting the regulatory focus from specific products and processes to assessing the strength of the systems that are meant to prevent and resolve manufacturing difficulties. This risk-based systems approach affords a broader scope to inspections, with the potential for significant business impact not only to individual products at a site but to all products that fall under the relevant quality systems. 			

Within FDA, definitions differ somewhat when applied to system-based inspection technique. The Center for Radiological Health (CDRH) was the first center to formalize a system-based inspection program through its quality system inspection technique (QSIT) compliance program, implemented in August 1999. CDER began a similar pilot program of the same name in January 2001, which has since been formalized as the Compliance Program Guidance Manual 7356.002. This manual is currently in use for inspections of all human drug facilities. The Center for Biologics Evaluation and Research (CBER) also is implementing system-based inspections for blood products under a new compliance program. 

The CDRH QSIT approach is based on seven major quality sub-systems: management controls; design controls; corrective and preventive actions; facility and equipment controls; material controls; records, documents, and change controls; and production and process controls. The CDER program is based upon six major sub-systems: facilities and equipment, materials, production, packaging and labeling, laboratory control, and the Quality System itself. The CBER blood product system-based inspection will be based on five sub-systems: quality assurance, product testing, donor eligibility, production and processing, and quarantine and inventory management. 

The CDER QSIT approach consists of dividing entire plant systems into the six distinct sub-systems mentioned above, following 21 CFR Parts 210 and 211. Although QSIT and the new draft guidance document are specific to drug and biological drug product manufacturers, they can easily and effectively be applied to active pharmaceutical ingredient (API) manufacturers. Each of the six quality sub-system categories identified by CDER may contain several subordinate systems. These six major quality sub-systems are the foundation for both full and abbreviated inspections. A full inspection requires evaluation of at least four of the QSIT-defined sub-systems, whereas abbreviated inspections require review of only two sub-systems. Companies that are new to FDA, have previously demonstrated noncompliance, or have a pending PAI usually undergo the full inspection. Firms with compliant histories and those that have recently been inspected (such as contract manufacturers who were recently inspected for different clients) may receive abbreviated inspections. The Quality System itself is part of every inspection.  

Beyond GMPs

GMP is the acronym for Good Manufacturing Practice. The GMPs represent a set of regulations that were promulgated as a final rule by FDA in 1978 and intended to ensure the safety and efficacy of the nation's drug products. The GMPs, as we know them today, are the result of over a century of actions by industry and reactions by government and consumer groups to bring guidance and controls to the food and drug industry, resulting in a safe supply of food and medicines.

Beyond GMPs: The Latest Approaches to Good Manufacturing Practices

				There continues to be much interest within industry and FDA about the future of the GMPs. Discussion groups have been spawned within professional organizations and at FDA to reevaluate the aging GMPs and associated guidance documents to ensure that the government does not impede technological progress, focuses its resources effectively, and upholds its mandate to protect the public. Although this trend is largely fueled by FDA's budgetary constraints, good things happen when we are reminded to focus on the essentials.

The present struggle within industry and among regulators is to sort out how best to grasp the essentials. FDA must grasp the essentials in order to translate them into regulations and guidance, and industry must grasp the essentials in order to translate them into best practice and consistent behaviors. So far, there have emerged several key themes. We can expect this lively dialog to lead to changes in how we answer the question: "Compliance with what?" 

The following is a brief discussion of these key themes that are changing how we think about compliance and several practical examples to elucidate the "mindful compliance" we seek to achieve. Beyond simple compliance with regulations, mindful compliance entails aligning our operations to ensure a data-driven state of control. 

Process knowledge is the collective awareness and experience of science and operations technology that ensure a product is manufactured and delivered in a manner consistent with its intended design. The more knowledgeable we are about our processes, the more we are able to control them and evaluate the impact of changes. 			

Consider the example of a medical device manufacturer that was proud of its progressive approach to managing its component suppliers. Suppliers were certified by facility audits and inspections of incoming attributes on the first ten lots received. Having cemented partnerships with its suppliers, the manufacturer accepted future shipments on the basis of the suppliers' certificates of analysis. However, when an investigation into field complaints for failing devices implicated a certified component, the supplier would not refund the manufacturer because the component met all of the agreed-upon inspection tests.  

The manufacturer failed to recognize that qualification of the supplier was not based on anything related to the component's performance in the final product. The manufacturer knew nothing about the supplier's process variability or statistical control. The manufacturer had not communicated requirements in terms that related to the functionality for this critical component. The qualifying audit was too general and largely relied on the fact that the supplier was ISO-certified. Additionally, the incoming attribute inspection was an ineffective predictor of the component's actual performance in use.  

The manufacturer had — and followed — a procedure for qualifying its suppliers. However, mindful compliance is based on process knowledge that is data-driven and statistically treated. In this example, loss to the manufacturer in terms of revenue and customer confidence could have been avoided by acquiring process knowledge and making a technical assessment of the supplier's capabilities. 

Risk knowledge is the collective awareness and experience of causes of unacceptable effects such as personal harm and financial loss, controls that eliminate risk or reduce it to acceptable levels, and metrics that detect trends toward failure. The more knowledgeable we are about risk, the more we can focus on the most critical aspects of the process and apply more rigorous process development, technical transfer, monitoring, and control. 							

Consider the example of a drug manufacturer of a liquid suspension. The manufacturer retrofitted the processing equipment of a decommissioned true-solution production line, which seemed like a cost-effective alternative. Mixers were added to all the tanks to ensure even distribution of the suspension in all mixing and holding vessels. The process was readily validated as the firm applied its long-standing process knowledge of liquid manufacturing. 			

Just days before the new product launch, a uniformity problem emerged. Batch records confirmed continuous tank mixing, and laboratory records confirmed that all testing was in control. Yet, across-the-lot sampling revealed portions that were subpotent and portions that were superpotent. 

The manufacturer failed to recognize that tanks were not the only place where even distribution of the suspension was necessary. Upon further investigation, it was discovered that there were periods when filling was stopped to deal with downstream filling issues. Although mixers kept the suspension adequately mixed in the tanks, there was no in-line mixing for the long process lines connecting the equipment train. Although process lines were thought to account for a relatively small proportion of the total volume, the settling of the suspension in the lines during lengthy down times effectively redistributed the active ingredient across the filled containers. 

The manufacturer complied with its policy to validate its manufacturing processes.  However, mindful compliance is based on identifying and controlling risks. Critical control points of the process are identified and validated, and data from these points are monitored in routine production to ensure continuous control. In this example, loss to the company and the potential for a patient adverse event could have been avoided by a disciplined approach to identifying and controlling risk based on process knowledge. 

Quality systems knowledge is the collective awareness and experience of designing, integrating, and implementing written business process instructions that drive consistent behaviors to meet requirements effectively and efficiently. A quality system stabilizes operations by ensuring that required practices are performed consistently and predictably yield the intended result. 			

FDA cited a biologics manufacturer for an excessive number of open investigations of process deviations and customer complaints. There were hundreds of open investigations, many of which had been open for over 90 days and several over six months. The company promised in its response to FDA to triage the backlog to close out the most important investigations in 30 days and the balance in 60 days. The procedure for conducting investigations was revised to require future investigations to be completed within 30 days. The revised procedure was part of the company's response to FDA. To management's surprise, FDA reported that a subsequent inspection following a customer complaint revealed that the situation remained essentially the same. The open investigations may have been different ones, but the numbers were just as high. 

The manufacturer failed to recognize that a revised procedure alone does not change behavior. Concerned about FDA enforcement action for the repeated citation, management conducted its own investigation into the failure to adhere to the new 30-day closure requirement. Many issues were discovered that required management's attention. Foremost was preponderance of the same deviations and complaints, pointing to a lack of thoroughness in investigations of the root cause of the problems. It was also noted that current protocols demanded the same degree of rigor for investigating a minor documentation error as a serious adverse event. Everything was given the same priority, and the system became clogged. Combined with administrative duplication and lack of accountability, it became apparent that the situation required far more attention than just a wording change in a procedure. 

The manufacturer had policies and procedures constituting a quality system. However, mindful compliance recognizes that policies and procedures of the quality system live in relationship to each other and within an overall management context. In this example, the potential risk to the consumer and the enforcement risk to the manufacturer could have been avoided by looking beyond a single procedure. The process of conducting an investigation needed streamlining, and the rigor of the investigation needed to be based on risk. There were also training and accountability issues. Management realized it needed a means other than FDA inspections to learn that the quality system was not functioning well. 

Management knowledge is the collective awareness and experience of applying the management arts in exercising its responsibility to adhere to applicable laws and regulations, meet customer expectations while economically controlling product quality, and provide dividends to stockholders. Management weaves together people and business processes that can acquire and utilize process knowledge, identify and control risks, and envelop the operation in a quality system. 			

Senior management of a drug manufacturer met offsite to review the state of the business and chart its future course. The finance, marketing, and sales departments gave presentations. Charts were projected and trends noted and explained. Data were compared to the previous quarter and year-to-date. The financial picture was less than optimistic, and this management group was tasked to respond. The company's quality improvement program suggested ways to reduce the cost of goods sold (COGS), accelerate the new product launch, and reduce associated costs. There was also the perennial challenge of reducing company headcount. 

Many of the suggested changes were pushed through and rewarded in order to capture the savings in the next quarter. Cheaper suppliers along with a progressive approach to getting them on the approved supplier list quickly netted material savings and a reduction in headcount in the auditing group. Launch quantities of the new product were projected to be ready three months early as a result of retrofitting existing equipment and using existing validation templates. These and other changes were greatly facilitated by the use of planned deviations while the quality department caught up with procedure revisions and paperwork. 

Management failed to recognize that it was creating the conditions for the loss of control — with financial and regulatory consequences far greater than the anticipated savings. Management lost touch with its process knowledge, risk knowledge, and quality system knowledge. Rather than directing its attention to achieving a greater understanding of the "sweet spot" where economic control of quality exists, suggestions were implemented without regard to the potential effects. Unfortunately, a perfunctory view of the quality system enabled the changes without challenging the effects of the changes and the probability of risk to the business. The quality system was viewed as a paper exercise. The financial loss from the delayed entry into the market was only exceeded by the long-term effect of being third to enter the market. 

The manufacturer had a management process to review trends and to authorize and implement initiatives to respond to business needs. However, mindful compliance requires that management possess knowledge that enables it to facilitate product and process integrity and detect and control unwanted variation. To accomplish this requires professionals who can design a quality system that is an asset to the business. Quality professionals must be able to develop, present, and defend quality system metrics relevant to the business. They must be diligent and objective guardians of process and quality system changes, requiring data-driven and risk-assessed changes. And they will first seek to reduce cost by implementing an efficient quality system, eliminating nonconformance and capturing cost savings, and promoting intolerance for repeated deviations with the same root cause. 

There is a shift to a compliance paradigm that is rooted in knowledge of process and risks. Arguably this may represent a swing to the middle ground between the historically science-based approach to inspections used by the biologics side of FDA and the more legalistic approach used by the drug side. This does not mean that one approach is right and the other is wrong, but it does mean momentum is building to grasp the essentials. 			

Good things happen when we are reminded to focus on the essentials. I say "reminded" because Deming, in 1931, said we need to continually search for better knowledge about materials, how they behave in manufacture, and how products behave in use. He proclaimed that economic manufacture requires statistical control of the process and measurements. Deming was a proponent for process improvement in every feasible way. 

This then is a short definition of mindful compliance: where the business of medical product manufacturing and the promulgation of regulations and guidance find a common ground of scientific and technological operations knowledge.  

 FDA. Guidance for industry, PAT— a framework for innovative pharmaceutical manufacturing and quality assurance. 2004 September. Available at: 

FDA. FDA unveils new initiative to enhance pharmaceutical good manufacturing practices: a risk-based approach. 2002 Aug 21. Press release available at: 

www.fda.gov/bbs/topics/NEWS/2002/NEW00829.html

  FDA. FDA announces new progress toward "21st century" regulation of pharmaceutical manufacturing. 2003 Sept 3. Press release available at: 

www.fda.gov/bbs/topics/NEWS/2003/NEW00936.html

 Shewhart W. Economic control of quality of product. Milwaukee (WI): American Society for Quality; 1989 (1931).

  Snyder J. Deemed and redeemed: principles of justification for deviation reviewers. 

  Snyder J. Preparing for FDA inspections: before, during and after. 

  Snyder J. Commentary: conference report. 

  Snyder J. Corrective and preventive action: planning to achieve sustainable GMP compliance. 

 Snyder J. Management responsibility for the quality system: a practical understanding for the CEO in FDA-regulated industries. 

John E. Snyder is president of John Snyder & Company, Inc., 245 County Road 4581, Boyd, TX 76023, 940.433.5044, 

Mindful Compliance

There continues to be much interest within industry and FDA about the future of the GMPs. Discussion groups have been spawned within professional organizations and at FDA to reevaluate the aging GMPs and associated guidance documents to ensure that the government does not impede technological progress, focuses its resources effectively, and upholds its mandate to protect the public.

BioPharm International-11-15-2004

Overview of GMPs

Why GMPs? What are GMPs and Why Do We Need Them?

Beyond GMPs: The Latest Approaches to Good Manufacturing Practices

Mindful Compliance: Where Knowledge and Regulations Meet