The American National Standard for Excipient GMP

Between September 2010 and December 2011, a joint committee organized by NSF International worked to complete a draft of NSF 363, a new American National Standard for excipient GMP. The draft standard, Good Manufacturing Practices (GMP) for Pharmaceutical Excipients, has completed the public comment period and a final version is to be balloted shortly (1). The new standard aims to establish industry-wide GMP requirements for the manufacture of excipients.

NSF 363 was developed based on the joint International Pharmaceutical Excipient Council and the Pharmaceutical Quality Group (IPEC–PQG) Good Manufacturing Practices Guide for Pharmaceutical Excipients (2). The suggestions expressed in the IPEC–PQG guide were reworked into requirements of the standard. Other IPEC guides are referenced in NSF 363 to clarify how industry can achieve conformance to the standard.

Background and importance of an excipient GMP standard

NSF is an independent, not-for-profit, nongovernmental organization and an Accredited Standards Developer of the American National Standard Institute (ANSI). ANSI is a private, nonprofit organization that administers and coordinates the US voluntary standardization and conformity assessment systems. ANSI is the US representative to the International Organization for Standardization (ISO). American National Standards are developed in conformance with the ANSI Essential Requirements to ensure that standards are developed through participation by those directly and materially affected without financial or organizational membership barriers, a lack of dominance by a single interest category, individual, or organization, and a balance of interests (3).

Of relevance to the industry is the fact that the National Technology Transfer and Advancement Act of 1996 requires that federal agencies adopt private-sector standards, particularly those developed by standards-developing organizations, wherever possible, in lieu of creating proprietary, nonconsensus standards. Further, the US Office of Management and Budget's Circular A119 provides for "Federal Participation in the Development and Use of Voluntary Consensus Standards and in Conformity Assessment Activities." As a result, FDA may adopt the ANSI standard GMP regulations for excipient ingredients manufactured for use in pharmaceutical dosage forms intended for US domestic markets.

The NSF joint committee organized to prepare the excipient GMP standard, designated as NSF 363, is comprised of representatives of excipient manufacturers, pharmaceutical users, and the general interests of the industry, including FDA, academia, and public health organizations. The final draft of NSF 363 was completed in the fourth quarter 2011 and was made available for public comment at the end of the year. The 45-day public comment period ended in January 2012, and the NSF joint committee reviewed the comments to the draft standard. Revisions to NSF 363 are in progress with final approval of the standard is expected to occur in the second quarter of 2012. Following the joint committee's approval, the standard will be considered by NSF's Council of Public Health Consultants with final approval by ANSI's Board of Standards Review. If approved as expected, the standard will be published by the end of 2012.

New excipient GMP requirements

Excipients come from a broad range of the chemical- and food-ingredient industries. Inorganic excipients usually begin with the mining of minerals. Excipients whose starting material is grown on a farm or forest are often further processed into a derivative through chemical reaction or fermentation. Synthetic excipients can be produced at the manufacturing site from basic chemical starting materials, such as ethylene and acetylene. The one process common to all excipient manufacturing is purification of the material to meet the requirements of a pharmaceutical ingredient. A key challenge of the NSF joint committee, therefore, was to develop excipient GMPs that would be applicable to the diverse operational activities of the excipient industry.

Risk assessment. NSF 363 represents the evolution of the joint IPEC–PQG GMP for Pharmaceutical Excipients (2) into an American National Standard suitable for regulation by FDA. The most significant new requirement in NSF 363 not found in the joint IPEC–PQG guide involves the use of risk management to ensure consistent excipient quality. For the purpose of the article, quality is taken to mean consistent excipient composition and freedom from contamination. Risk assessment is defined in NSF 363 as "a systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards" (1). (For details on conducting and documenting risk assessments as required by the standard, please see the article "Conducting Risk Assessment in Support of ANSI Excipient GMPs" in this issue.) The IPEC–PQG excipient GMP guide, as well as other IPEC guides, provide additional resources for risk assessment. The purpose of the many risk assessments stipulated in NSF 363 is to identify risks to excipient quality to assure control measures are commensurate with those risks (1). Several sections and clauses of the new standard are explained below. Note that the term "Section" as used in this article refers to requirements that also contain enumerated subordinate requirements referred to herein as "Clauses."

The first clause in NSF 363 to refer to risk is 4.2.1 (Quality Management System/ Documentation Requirements/General) where the appropriate use of quality risk-management principles, defined as a systematic process for the assessment, control, communication, and review of risks to the quality of the excipient across its life cycle, are to be used to evaluate changes to the quality management system. Such changes include activities, operations, and processes that pose a risk to excipient quality. Also in this clause is the requirement to document a risk assessment that justifies those other clauses of the standard that do not apply to excipient manufacture and are thus not implemented.

Section 4.3 on Quality Management System/Change Control requires the implementation of risk assessment as a tool to determine the impact of change involving the manufacture of the excipient. Here, IPEC–Americas has provided a guide as a basis for conducting the risk assessment. Any change that may impact the consistent composition or performance of the excipient should be considered potentially significant and the pharmaceutical customer should be notified as suggested in the IPEC guide for significant change reporting (4).

Section 6 on Resource Management requires several risk assessments to identify the potential for contamination of the excipient. For example:

• Clause 6.2.3 (Human Resources/Hygienic Practices) describes risk assessment to identify the potential for contamination of the excipient by personnel and/or their activities. Where a risk to the excipient exists, the standard provides five measures that may be taken to minimize said risk. The proposed control measures will be familiar to manufacturers who have implemented excipient GMPs as noted in the IPEC–PQG guide (2).

• Clause 6.3.1 (Infrastructure/Buildings and Facilities) requires risk assessment to evaluate the threat to excipient contamination posed by the buildings and facilities. This assessment is to consider the intended use of the excipient (i.e., oral, parenteral, topical applications, etc.). The five aspects presented for consideration are discussed in the IPEC–PQG guide (2). The provision to perform the risk assessment relative to the marketed intended use of the excipient links how the excipient is marketed to the tolerance for risk of contamination from the manufacturing facility.

• Clause 6.3.3 (Utilities) stipulates evaluation of contamination risk from utilities but does not require linkage to the intended use of the excipient.

• Section 6.4 on Work Environment requires the assessment of contamination risk from exposure to the work environment. This risk assessment is linked to customer requirements and marketed use. The standard notes five control measures that are to be considered when conducting this assessment for risk. The clauses under 6.4 require documentation of conformance to the control measures implemented to address the risk to excipient quality noted in the assessment. However, Clause 6.4.4 (Pest Control) provides for a risk assessment to identify the elements needed in a pest control program.

Section 7 on Excipient Realization, further provides for risk assessments, as follows:

• Clause 7.4.1 (Purchasing/Purchasing Process) requires the identification of quality-critical materials and services through risk assessment. The requirements of this clause are applicable only to those materials and services identified as quality-critical, except for the general expectation to have an agreed specification from approved suppliers. While neither the standard nor the IPEC–PQG Excipient GMP guide provide criteria for the determination as to whether a material or service is quality-critical, the assessment should be based on the potential impact to excipient quality (2). The suppliers of quality critical raw materials should be expected to notify the manufacturer of a process change so that the excipient manufacturer can evaluate the change for the potential impact to the excipient.

• Clause 7.5.5.1 (Production and Service Provision/Preservation of Product/Raw Material Packaging Systems) requires a risk assessment to assure the storage and handling of raw materials provides suitable protection against deterioration or contamination and that identification labels remain legible.

• Clause 7.5.5.2 (Production and Service Provision/Preservation of Product/Excipient Packaging Systems) provides for a risk assessment only where reusable containers are returned for further use.

The only requirement for risk assessment in Section 8, Measurement, Analysis and Improvement, is in clause 8.3.2 (Control of Nonconforming Product/Reworking). Here, a risk assessment is required to assess the risk of the rework operation to excipient quality.

In conclusion, the provisions for risk assessment in NSF 363 are new in that they are to be formally conducted and documented. Informal assessment of risk to excipient quality has always been an expectation in IPEC excipient GMP guides however.

Other noteworthy requirements. Several other provisions in NSF 363 are either new to excipient GMP requirements or differ from that suggested in the IPEC–PQG Excipient GMP guide (2). In particular, the excipient manufacturer should be aware of the following differences.

Clause 4.2.4 (Quality Management System/Documentation Requirements/Control of Records) requires that records be kept for 1 year beyond the excipient expiration date or first re-evaluation date. The standard further states that where the manufacturer does not stipulate a re-evaluation or expiration date, the records should be retained for five years. The IPEC-PQG Excipient GMP guide merely suggests keeping records for a defined period.

Specified responsibilities of an independent Quality Unit are noted in Clause 5.5.1 (Management Responsibility/Responsibility, Authority, and Communication/Responsibility and Authority) with allowance to delegate some duties. While these responsibilities are also listed in the IPEC–PQG Excipient GMP guide as is allowance for delegation, the standard further notes that ultimate responsibility for oversight and approval remains with the Quality Unit.

As noted, Clause 7.4.1 (Purchasing Process) requires the identification of quality-critical materials and services. However, unlike the IPEC–PQG Excipient GMP guide, the standard specifically includes packaging materials. Also where the guide notes that periodic audits may be required, the standard notes the assessments are to be ongoing. The expectation of the standard is for the manufacturer to continuously monitor the conformance of these suppliers to the purchasing agreement.

Clause 7.4.3 (Purchasing/Verification of Purchased Product) adds several new requirements:

• Justification for not sampling any incoming material

• Verification of the measurements reported on the supplier Certificate of Analysis (COA)

• Verification that the Certificate of Conformance for packaging components references the current agreed specification.

Section 7.5 on Production and Service Provision, also contains several new provisions:

• Requirements for equipment and utensil cleaning and sanitization are expanded under clause 7.5.1 (Control of Production and Service Provision). In addition to the expectations noted in the IPEC–PQG guide, the standard requires the establishment of criteria to confirm cleaning effectiveness, requires chronological records of cleaning activities and identification of the cleaning status of equipment.

• There is a requirement to demonstrate ongoing evidence of process capability under Clause 7.5.2 (Validation of Processes for Production and Service Provision).

• Clause 7.5.3 (Identification and Traceability) stipulates documentation that defines identification and traceability for raw materials in continuous processing. The IPEC-PQG guide suggests using the time material was processed for traceability. This clause also requires that labeling include the manufacturing address or a reference to the site of manufacture.

• Under Section 7.5.5 on Preservation of Product, the manufacturer is expected to justify the handling and storage conditions for quality critical materials.

• Where excipient is shipped in bulk, there is to be a list of restricted or allowed previous cargoes for non-dedicated bulk transport equipment according to Clause 7.5.5.3 (Excipient Delivery).

Section 7.6, Control of Monitoring and Measuring Equipment, describes the expectations for measuring and test devices used to make quality-critical measurements.

There are several new expectations under Section 8.2.4, Monitoring and Measurement of Product:

• Clause 8.2.4.1.1 (Laboratory Controls) adds the requirement to provide documentation of sample preparation to show conformance with the test method. In addition there is a requirement to reference the test method. This documentation will facilitate the investigation of Out-of-Specification test results.

• Clause 8.2.4.1.2 (Laboratory Procedures) notes that reagents and test solutions are to have expiration or re-standardization dates.

• Clause 8.2.4.5 (Certificate of Analysis) includes the provision noted in the IPEC–Americas COA guide to include the "manufacturer's name and site of manufacture or reference to the site of manufacture" (5).

Section 8.3 on Control of Nonconforming Product, adds a couple of requirements:

• Nonconformance is to be investigated to identify the root cause and potential impact to other batches or products.

• Under Clause 8.3.2 (Reworking) customers are to be notified if they are provided with a reworked batch. Such material represents a potential significant change since routine processing was not followed.

The last addition of note is in Section 8.4 on Analysis of Data, which requires monitoring of nonconformance with this standard and of supplier nonconformance are new requirements.

Conclusion

This article highlights the new requirements for excipient GMP as reflected in NSF 363. It expresses the opinion of the author as to what requirements in the draft ANSI excipient GMP standard differ from the IPEC–PQG Excipient GMP Guide. It is important to note that at the time this article was prepared, the public comment period for the standard had just been completed. Based upon input, requirements as described here may be modified. The reader is thus urged to review the requirements in the approved NSF 363 standard for applicability to their manufacturing operation. While certain new requirements are expressed in the standard, they either evolved from implied expectations in the excipient GMP guide or are enhancements resulting from the current business and regulatory climate. NSF 363 is organized in accordance with ISO 9001 but adds new clauses where appropriate. The organization of this American National Standard will facilitate submission of the standard to ISO for their adoption as a global standard.

Irwin Silverstein, PhD, is vice-president and chief operating officer at International Pharmaceutical Excipients Auditing, 1655 N. Fort Myer Drive, Suite 700, Arlington, VA 22209, tel. 703.351.5266.

References

1. NSF Joint Committee, Draft Good Manufacturing Practices (GMP) for Pharmaceutical Excipients (2012).

2. IPEC–PQG, Joint IPEC–PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients (2006).

3. ANSI, Essential Requirements: Due Process Requirements for American National Standards.

4. IPEC–Americas, Significant Change Guide for Bulk Pharmaceutical Excipients (2009).

5. IPEC–Americas, Certificate of Analysis Guide for Bulk Pharmaceutical Excipients (2000).