by Rick Calabrese, A. Mark Trotter, and Luke T. Foo
ISO 9001 and GMPs: What to Look For
- Develop a quality policy.
- Develop a quality manual.
- Document the management’s responsibility.
- Set up a management review program.
- Appoint a management representative.
- Establish quality planning.
- Establish a customer focus.
- Establish a corrective and preventive action system.
- Establish quality metrics.
- Implement an internal audit program.
- Establish a quality control unit.
- Develop component control procedures.
- Develop specific process-control procedures.
- Establish a complete validation and qualification program.
- Establish a cleaning process.
- Establish a process-based system.
- Establish appropriate methods.
- Establish an equipment policy.
- Ensure a safe and regulated facility.
- Establish a regulatory system that prepares personnel and operations to be compliant as a legal requirement.
Quality systems are an important part of most businesses, and this is especially true within the drug industries. These systems ensure that companies follow an accepted standard of quality when planning and manufacturing their products. In the United States, the federal government requires drug companies to comply with the good manufacturing practices (GMPs) that are regulated through the U.S. Food and Drug Administration (FDA). Compliance with these is required for commercialization of all drug products. The more generic, internationally accepted quality management system standard is ISO 9001, which is maintained by the International Organization for Standardization. Companies that market in both the United States and other countries, or that deal with vendors or subcontractors that aren’t regulated by the FDA, need to be aware of the relationship between the two.
Significant quality management benefits can be obtained from a GMPs-registered company if it chooses to comply with the ISO 9001 standard. Conversely, aside from the legal requirements, significant product quality advantages can be gained for an ISO 9001-registered company if it incorporates GMPs into its system. These advantages can lead to quality and efficiency improvements, which then translate into a competitive market advantage.
This article summarizes the backgrounds of ISO 9001 and the GMPs, compares and contrasts them, and then discusses how to become compliant with both.
ISO 9001 is a process-focused quality management system (QMS) standard that requires all quality system processes to be measured, monitored, controlled, and improved. Business and quality objectives must be established for relevant functions at appropriate levels, and these must be measurable. When objectives are measured, the quality system’s effectiveness is verified by achieving those objectives.
QMS planning requires top management to review the system to ensure its continuing suitability and effectiveness. This is accomplished through periodic management reviews during which management assesses opportunities for improvement and affects the appropriate changes.
In short, the ISO 9001 QMS, with its process focus, requires measurable improvement toward specific business and quality objectives that go beyond simply maintaining a well-documented management system.
The regulation of foods and drugs in the United States began with Congress passing the Food and Drug Act in 1906. It focused on accuracy and truth in product labeling.
In 1937, a Tennessee drug company marketed a liquid form of the new sulfa wonder drug, Elixir Sulfanilamide. The solvent in this untested product was a highly toxic chemical analogue of antifreeze; more than 100 people died, many of them children. The public outcry helped to propel the Federal Food, Drug, and Cosmetic Act through Congress in 1938. It mandated that new drugs be safe, and that manufacturing methods, facilities, and controls be adequate. It also mandated quality and identity standards for foods, prohibited false therapeutic claims for drugs, clarified the FDA’s right to conduct factory inspections, and controlled product advertising.
In 1962, when a sedative called Thalidomide caused thousands of deformed newborns in western Europe, a new law mandated safety as well as efficacy before a drug could be marketed. The law established good manufacturing practices for the drug industry, and granted the FDA greater powers to access company production and control records to verify those practices. In 1978 the final draft was submitted to the public for comment, and in 1979 the first drug GMPs became effective. For more information see A Historical Guide to the U.S. Government, edited by George T. Kurian (Oxford University Press, 1998).
There are similarities between the ISO 9001 standard and drug GMPs regulations. Both require:
• Written records and procedures appropriate to the processes taking place
• A control process for these records and procedures
• That personnel are properly trained and qualified to perform their jobs
• That work environments are properly maintained
• That customer complaints and nonconformances are addressed, and that appropriate corrective actions are taken to prevent recurrences
• That equipment be maintained and calibrated
• That products be properly identified throughout the manufacturing cycle
• That there be product release pro--
cedures, analysis of product, and conformance to specifications prior to release
• Appropriate quarantining and control of nonconforming product to prevent its release to the marketplace
• The application of good scientific principles and statistical techniques
The first difference doesn’t have to do directly with the standard but rather with how it’s set up. The most obvious difference is that when a company manufactures therapeutic products that are sold or distributed in the United States, it is legally required to comply with GMPs. There are no legal requirements in the United States for any company to be specifically compliant to the ISO 9001 standard. GMPs are regulations that are enforceable by law, and there can be severe business and criminal penalties if they’re not followed. GMPs are administered and enforced through the federal government by the FDA. Companies that manufacture therapeutic products must register with the FDA annually. Companies certified to ISO 9001 are audited annually by registrars that are qualified by the ISO governing body to oversee and audit client companies. Certifications are granted for three years between renewals.
There are differences between the actual written standard and regulations as well. Most obvious is that Title 21, Code of Federal Regulations (FDA 21 CFR), Parts 210 and 211 are specific for manufactured drug products. ISO 9001 isn’t specific to any one industry or product line.
There are also inspection differences. The “c” in cGMPs stands for “current” and allows FDA inspectors latitude to assess compliance to the regulations. New or current interpretations may have been accepted as enforceable industry practices even though they’re not called out specifically in the written regulation. On the other hand, an ISO 9001 auditor can audit only to the letter of the last release of the standard.
GMPs list more detailed requirements for process controls, facilities, and equipment than ISO 9001 does. Requirements for validating processes are also described in greater detail in the GMPs than in ISO 9001. These include validation for equipment, facilities, methods, cleaning, software, and electronic systems—all covered in FDA 21 CFR Part 11.
Although both require management oversight, only ISO 9001 describes in detail the requirement for a management review. This requirement specifically lists what needs to be discussed during each review.
ISO 9001 requires that a management representative oversee the QMS. It doesn’t specify a quality control unit that shall have the responsibility and authority to approve or reject product, as do the GMPs.
The most distinctive difference is that ISO 9001 requires measurement of the effectiveness of the quality system and customer satisfaction. FDA 21 CFR Parts 210 and 211 are more narrowly focused and are designed to ensure that the final drug product is safe, pure, and effective.
Measurements required in these GMPs confirm the “identity, strength, quality, and purity of the drug product.” There’s no mention of a quality system or of customer satisfaction; the GMPs emphasize written procedures, deviations from those procedures, record keeping, production, and process controls.
GMPs emphasize safety and efficacy. ISO 9001 emphasizes effectiveness of a quality management system in meeting customer requirements. Despite this semantic difference, the results of complying with the requirements of either one should be a safe and effective product. Nevertheless, compliance to one doesn’t automatically bestow recognition of compliance to the other. In other words, an ISO 9001-certified organization must undergo an FDA premarket inspection before commercializing a drug. Being ISO 9001-certified, however, should increase the likelihood of avoiding nonconformances in an FDA premarket inspection if certain GMPs’ specific requirements are met. Success depends largely on being prepared for the difference in emphasis.
The first significant difference is that GMPs require the formation of a quality control unit. This must have the responsibility and authority to approve and reject product. ISO 9001 calls for a management representative who has the authority to administer the standard. The standard doesn’t grant the same power to approve and reject product that’s granted in the GMPs to the quality control unit.
GMPs don’t require a management review, quality policy, quality manual, or quality audits. Neither do they specify a supplier evaluation program or a purchasing process. However, they do require that the buildings and facilities meet stringent specifications for size, ease of cleaning and maintenance, contamination prevention, filtration, ventilation, heating and cooling, control of penicillin, lighting, plumbing, sewage and refuse, washing and toilet facilities, and general sanitation. There are similarly specific requirements for equipment, including reactivity of surfaces that must not alter the safety, identity, strength, quality, or purity of the product.
If an ISO 9001-certified organization doesn’t include the GMPs specifics noted above, it won’t be GMPs-compliant despite being ISO 9001-certified.
Whereas certification to ISO 9001 applies to the QMS for products in general, the CFR Parts 210 and 211 are specific to manufacturing drug products. Therefore, the quality procedures and drug-product attributes are clearly defined as required by law and enforced by the FDA. Compliance to GMPs provides manufacturers with the tools and conformances to meet ISO 9001 more easily than compliance to ISO 9001 does to meet GMPs.
• For a GMP system, a manufacturer would have to create a quality control unit with more responsibility and authority than a management representative as required by ISO 9001.
• Under GMPs, all quality documents are considered legal documents, and companies are required to keep them for at least one year past a product’s expiration date.
• GMP companies would have to develop metrics and procedures for measuring the effectiveness of their quality programs. They would also have to develop programs for capturing and addressing customer- satisfaction issues.
• A GMP system would have to establish a management review program, as required by ISO 9001.
• ISO 9001 companies would have to create the required systems processes and procedures required by the GMPs, which are more product-specific.
• Employees familiar with the ISO 9001 standard would have to be trained and made fully aware of the legal responsibilities inherent in GMP registration.
ICH Q10—“Pharmaceutical Quality Systems,” a new International Conference on Harmonization draft guideline model for implementing an effective quality management system in pharmaceutical companies, was released in May 2007 to harmonize three regulatory regions—the European Union, Japan, and the United States. (See ICH Q10—“Pharmaceutical Quality Systems,” Draft Guidance, Step 2, May 9, 2007.)
The ICH Q10 document offers a comprehensive approach to quality systems and is based on existing regulatory guidance and industry standards from ISO, ICH, and GMPs. (See U.S. FDA Guidance for Industry Concerning Quality Systems Approach to Pharmaceutical current GMPs Regulations and 21 CFR Parts 210 and 211; ICH 7 Good Manufacturing Guidance for Active Pharmaceutical Ingredients.) The proposed guideline will apply to pharmaceuticals, biologicals, and biotechnology therapeutics beginning with drug approval and continuing through to marketing date and discontinuance. ICH Q10 is designed to augment rather than replace or substitute current regulations and standards, while harmonizing with the regional guidance. When one is implementing ISO 9001 and GMPs, this ICH Q10 document will ease the burden of, and provide guidance for, the process.
The expected benefits of successfully integrating the aforementioned standards are significant returns on investment by reducing the costs of drug manufacturing and delivery, coupled with enhanced process efficiencies.
The GMPs and ISO 9001 have converged from two distinct beginnings to establish guidance to better business and regulatory practices. Better-quality drug products, reduced drug shortages, minimizing validation and compliance documentation, and speeding products to market are a few major benefits of this harmonization.
Compliance to both standards as well as the ICH Q10 guidance can help an organization provide superior products, processes, and invaluable customer service. This will result in a safer and healthier drug-product pipeline and an improved financial bottom line for the industry.
It’s important to note that, no matter which quality approach is followed, good science and its application to company processes is paramount to the success of the quality program.
GMP companies have a slight edge when becoming registered to ISO 9001. Whereas ISO 9001 applies to the quality management systems for products in general, FDA 21 CFR Parts 210 and 211 are specific to manufacturing drugs. Therefore, the quality procedures and drug-product attributes are clearly defined as required by law and enforced by the FDA. This compliance provides manufacturers with the tools and requirements to meet ISO 9001’s requirements more readily than ISO 9001 compliance does for GMPs compliance.
GMPs operations would strongly benefit from adding ISO 9001-required quality measurement and customer satisfaction programs.
ISO companies would benefit from the GMPs’ systems control and documentation requirements, and the product would benefit from the GMPs’ standards to demonstrate “safety, strength, quality, and purity” of the final drug product.
It’s possible for a company to adhere to both standards and achieve full compliance to each.
Rick Calabrese is the corporate quality manager for Sartorius Group North America. He holds a bachelor’s degree in geology and a master’s degree in industrial management, both from SUNY Stony Brook. Calabrese has more than 20 years of experience in quality within the pharmaceutical industry, and more than 12 years of experience in performing both internal and external audits.
A. Mark Trotter is the business development and training manager for Sartorius Stedim Biotech Inc. He completed his postgraduate studies at Long Island University, earning a master’s degree in medical microbiology and an MBA. Trotter has an extensive background in the biopharmaceutical sciences coupled with regulatory knowledge that supports his expertise in process validations.
Luke T. Foo is the quality assurance/quality control director at Spectrum Pharmaceuticals in Irvine, California. He has a bachelor’s degree in pharmacy from the Brooklyn College of Pharmacy and a master’s degree in management systems analysis from Kean University. Foo has more than 30 years of pharmaceutical/biotechnology experience in manufacturing, product development, and quality assurance.