cGMPS: Yesterday, Today and Tomorrow

Harmonizing extant FDA regulations and international cGMPs

By Debbie Thomas

The FDA published a final rule containing a summary of changes to its current Good Manufacturing Practice for medicinal products on September 8, 2008 in the Federal Register. These changes are codified in 21 Code of Federal Regulations (CFR) Parts 210 & 211, “Current Good Manufacturing Practice (cGMP) Regulations for Finished Pharmaceuticals.” The changes cover areas of manufacturing, quality control, and documentation. The final rule became effective on December 8, 2008. The rule, the agency says, is the “first increment of modifications” to Parts 210 and 211, as FDA compares existing quality systems regulations in the U.S. and internationally for updating cGMP guidance.

Photo courtesy of West Pharmaceutical Services

Background on Amendment to cGMP Regulations for Finished Pharmaceuticals

The FDA amended the regulations in an attempt to modernize or clarify some of the requirements that are already in existence. As part of an incremental approach, the FDA is seeking to harmonize 21 CFR Parts 210 and 211 with other regulations and international cGMP standards where possible. The FDA has stated that this final rule is intended to update the codified language in order to reflect current practices. At the same time, the amendment does not impose any additional requirements. The FDA also believes that these amendments increase latitude for manufacturers in complying with existing cGMP requirements, thereby making conformity with these requirements less onerous.

The “Pharmaceutical cGMPs for the 21st Century,” a risk-based initiative, provided for the creation of a cGMP Harmonization Analysis Working Group to perform a formal analysis of 21 CFR 210 and 211 against European Union GMPs, The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (jointly referred to as PIC/S) and other cGMP regulations within the FDA, such as the Quality System Regulations (21 CFR 820). The cGMP Working Group was chartered to review and compare the cGMP requirements to identify the differences and consider the value of changing or supplementing the extant regulations. In their analysis, they found that there were far more similarities than differences among the various regulations. As a result of the analysis, the FDA has started an incremental approach to modifying parts of 21 CFR 210 and 211. The goal of modifying the regulations is to modernize or provide further clarification of some of the requirements and harmonize various aspects of parts 210 and 211 with other FDA regulations and international cGMP standards.

Brief History of cGMP Regulations

The FDA developed cGMP regulations for drug products in 1962. These cGMP requirements provide a uniform standard for the entire industry to have systems in place to assure the proper design, monitoring, testing, and control of manufacturing processes and facilities. cGMP regulations assure the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations to meet specific requirements. The requirements include establishing strong quality management systems, robust operating procedures, obtaining appropriate quality raw materials, detecting and investigating product quality deviations, and maintaining reliable testing laboratories. When a pharmaceutical company implements a cGMP system, it helps prevent contamination, mix-ups, failures, deviations, and errors, minimizing the potential for harm. This assures that drug products meet quality standards. cGMPs are minimum requirements; a company can also do more. In fact, many pharmaceutical manufacturers have modern quality systems and risk management approaches that exceed cGMP minimum standards.

Future of cGMP Regulations

The FDA periodically reassesses and revises the cGMP regulations to retain their flexibility, allowing manufacturers to implement the controls needed by using scientifically sound design, test procedures, and processing methods. This flexibility in the regulations is intended to accommodate the use of advances in modern technology and other scientific knowledge to continue to safeguard the drug manufacturing process and the public heath. This also allows for innovative approaches to achieve higher quality through continual improvement. Consequently, the “c” in cGMP means “current.” This gives companies the ability to use technologies and systems that are current to comply with the regulations.

FDA Expectations of cGMP Compliance

The FDA’s requirements are mandatory for companies, and the FDA fully expects companies to follow these regulations. We must keep in mind that these regulations are the minimum cGMPs in manufacturing, processing, packing, or holding of drugs. More specifically, this includes the very minimum cGMPs for methods to be used in, and the facilities or controls to be used for, the manufacturing, processing, packing, or holding of a drug. These regulations are meant to assure that the drug meets the requirements of the Federal Food, Drug, and Cosmetic Act (FD&C Act) with regard to the drug’s safety, identity and strength. This compliance ensures that the drug meets the quality and purity characteristics that it purports or is represented to possess.

Adulteration

Failure to comply with any regulation in the manufacturing, processing, packing, or holding of a drug product can cause the drug to be “adulterated” for purposes of the FD&C Act. Therefore, if a company is not complying with cGMP regulations, the drug is considered “adulterated” under the law. This means that the drug was not manufactured under cGMP compliance. It does not necessarily mean that there is something wrong with the drug. In addition, the person or manufacturer responsible for the failure could be subject to regulatory action.

21 CFR 210 & 211 Amendments to cGMP Regulations for Finished Pharmaceuticals

The final rule revised cGMP requirements predominantly focusing on the following:

• Aseptic Processing
• The Use of Asbestos Filters
• Verification of Performance of Operations by a Second Individual

Aseptic Processing

Author note: Changes in the section reference are in bold with subsequent commentary to explain the modifications.

21 CFR 211.67 Equipment cleaning and maintenance


As noted above, in 21 CFR 211.67(a), the FDA added the phrase “and/or sterilized” after the word “sanitized” to reflect the fact that sterilization is appropriate for sterile drug products. The regulation states that for equipment and utensils utilized in sterile drug processing, there are times that sanitization is appropriate, while for other equipment and utensils, sterilization is appropriate. For others, both sanitization and sterilization are appropriate in order to prevent contamination of the drug product.

21 CFR 211.84 Testing and approval or rejection of components, drug product containers, and closures


21 CFR 211.84(d)(6) was amended to read as referenced above. The agency removed the phrase, “that is liable to” and replaced the phrase “with potential for” to clarify a longstanding interpretation of the regulation. Each lot of component, drug product container, or closure that is susceptible to contamination must undergo microbiological testing before use.

21 CFR 211.94 Drug product containers and closures


The revision added a provision requiring the validation of the depyrogenation processes for drug product containers and closures. The FDA stated that a reason to add this provision was that it has been a long-standing industry practice to validate the depyrogenation used for drug product containers and closures to ensure consistent removal of microbial contamination and pyrogens or endotoxins.

21 CFR 211.110 Sampling and testing of in-process materials and drug products

1. Tablet or capsule weight variation;
2. Disintegration time;
3. Adequacy of mixing to assure uniformity and homogeneity;
4. Dissolution time and rate;
5. Clarity, completeness, or pH of solutions;
6. Bioburden testing.

The amendment to section 211.110(a) added bioburden testing to the list because testing for bioburden is standard industry practice for in-process materials and the drug products that are produced by aseptic processing. The FDA said testing for bioburden is an important in-process control. They continued to say that they believe that there is enough flexibility written into the regulation for manufacturers so that the requirement to conduct bioburden testing, where appropriate, would be done to assure batch uniformity and drug product integrity.

21 CFR 211.113 Control of microbiological contamination


21 CFR 211.113(b) was amended to provide clarification on the requirement that there needs to be procedures on the validation of all aseptic processes, in addition to sterilization processes.

The FDA received many comments about this clarification, which noted that aseptic processing could not be validated, and that media fills did not validate aseptic processing. The FDA acknowledged that aseptic process validation does not provide absolute assurance of product sterility, but did not agree that the processes cannot be validated. The agency elaborated on the response, explaining that the validation of aseptic processes is a common practice throughout the pharmaceutical industry and that it means establishing documented evidence that provides a high degree of assurance that a particular process will consistently produce a product meeting quality attributes and specifications, where they have been predetermined. The FDA’s response also stated that media fills, operational controls, and product sterility testing do provide a sufficient level of assurance that drugs purported to be sterile are in fact sterile.

The Use of Asbestos Filters

The revision to 21 CFR 210.3(b)(6) and 211.72, states that asbestos filters used in processing injectable products are no longer permitted; this also includes any limited use. The language in the amendment makes it very clear that these types of filters are strictly prohibited. Previous language stated that manufactures should, before using an asbestos-containing filter, submit proof to FDA that an alternative non-fiber releasing filter will, or is likely to, compromise the safety or effectiveness of the product. Comments to the agency indicated that this language may be interpreted as permitting the use of these types of filters, which could pose a risk to patient safety. In reaction to comments received by the FDA the passage “the use of an asbestos-containing filter is prohibited” has now been added. This decision seems to be in line with the general reduction and elimination of the use of asbestos not only within this industry but also worldwide.

Verification of Performance of Operations by a Second Individual

The FDA added language to acknowledge that certain operations in manufacturing can be performed by automated equipment and verified by a single person, rather than having one person perform the operation and a second person verify the operation. It is still a requirement for a human to verify that the systems are operating as planned and that they are monitored for abnormalities. The level, nature, and frequency of the human verification will vary depending on the level of automation used and nature of the system and controls. They continue to believe that human verification is necessary to ensure that automated systems are functioning properly. This revision clarifies their longstanding position that one human check is verification of a processing step performed by automated equipment.

In particular, the FDA added language in Section 211.68(c) which states that automated equipment can be used to perform operations and a second person can verify the equipment in the following operations: Section 211.101(c) and (d): charge-in of components and containers; Section 211.103: calculation of yields; Section 211.182: equipment cleaning and maintenance; and Section 211.188(b)(11): batch production and control records.

While the FDA addressed this issue in the 1978 preamble to the final rule, it decided to give additional clarification by amending these sections because of the widespread and increased use of computer-controlled operations. Additionally, there were several comments to the FDA about the need for human verification of operations that are performed by validated computer systems. The FDA’s response was that although increasingly sophisticated controls and safeguards have been implemented for some automated systems, the agency still believes that some degree of human oversight, supervision, verification, monitoring or checking is necessary to verify proper performance of the equipment.

Next Steps for Pharmaceutical Manufacturers

Each manufacturer should ensure that it complies fully with the intent of the regulations. This can be done by performing an evaluation of all manufacturing operations subject to specific cGMP requirements in the regulations. Manufacturers can perform an internal “mock audit” or have an independent third-party audit. In all cases, when manufacturers find non-compliance or a deficiency, it should be corrected immediately. Again, since there are no newly imposed requirements, the FDA’s expectations are that manufacturers must be in compliance. This type of activity is not new to any pharmaceutical manufacturer. Internal or third-party auditing is a function that is essential to any cGMP operation. These types of activities serve to provide not only an assurance of immediate compliance, but also to develop and foster an ongoing culture of compliance.

What To Look for from Primary Component Suppliers

Pharmaceutical companies interested in providers who offer component preparation and component sterilization processes need to ensure that the Supplier is in good standing and is cGMP compliant. Components should be manufactured and prepared using documented and validated processes that comply with cGMP requirements. The processes should also meet applicable international standards.

No matter which provider a company decides to choose, where component washing is required, there should be evidence that the wash process has been validated to achieve a minimum three-log bacterial endotoxin reduction. The qualified and validated process should support control of endotoxin level, bioburden, and if applicable, particle level and item-specific silicone oil level. Each characteristic should be tested for each washer load (each lot) and denoted on a Certificate of Analysis, which should accompany each shipment. For component sterilization, companies need to ensure that the components have a fully validated sterilization process that meets current industry and regulatory standards.

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Some of the information/commentary is paraphrased from the federal register notice and FDA website:

Food and Drug Administration Website: www.fda.gov (2009)

Federal Register / Vol. 73, No. 174 / Monday, September 8, 2008 / Rules and Regulations, pgs. 51919 – 51933

Debbie Thomas is vice president of Regulatory Affairs for West Pharmaceutical Services. For more information about West products, please visit www.westpharma.com