Developing an NHP-relevant Quality System

BY JERRY HIRSCH, PHD

Natural Health Products (NHPs) are a growing industry in North America. Uncertainty of NHP quality, however, has been identified as a crucial impediment to market growth and realization of potential health benefits. Consumer confidence in the quality, composition and lack of adulteration of NHPs can increase if manufacturers, distributors, importers, retailers and others address the complex underlying problems associated with ensuring product quality.
Health Canada created the Natural Health Products Directorate (NHPD) several years ago to address NHP research and regulatory issues to ensure that NHPs are safe, efficacious and of good quality. Canada recently passed regulations addressing the manufacture and sale of NHPs that include compliance with Good Manufacturing Practices (GMPs) as part of product quality and licence requirements. This paper will describe the basic requirements that must be met to sell NHPs in Canada, some of the analytical challenges and developments, and outline a basic quality system to help ensure product composition and quality.
Companies must obtain a site licence, which authorizes them to perform activities related to the manufacturing, packaging, labelling or importing of NHPs. In addition to providing basic information about the company, they must submit a quality assurance report completed by a qualified QA person. The QA report assesses the company’s ability to meet the GMP requirements in Part 3 of the NHP regulations in describing the premises, personnel, processes — such as the sanitation program — and product specifications. This involves developing Standard Operating Procedures (SOPs) and maintaining various records relating to personnel, testing of ingredients, equipment and other issues.
Manufacturers, labellers and importers must also obtain a product licence which sets out the specific product characteristics that NHPD has authorized for sale of the NHP, such as the brand name, recommended dosage, route of administration, source of the material and the use or purpose. Applicants must provide product specifications for each ingredient, a quantitative list of non-medicinal ingredients and a product label. Another key requirement is the provision of data to support safety and efficacy of the NHP when used as directed.

Special Analytical Challenges Relating to Analysis of NHPs

NHPs are often difficult to analyse, thus presenting huge challenges to industry and contract laboratories. Some of the challenges
include:

• NHPs consist of complex botanical entities in a wide variety of matrices exerting multiple interrelated pharmacological effects. While pharmaceutical drugs are typically comprised of well-defined synthetic compounds that are consistent from batch to batch, NHPs are composed of potentially thousands of chemicals that may vary significantly regardless of manufacturing practices.


• Products are not well-characterized or standardized in terms of chemical content and pharmacological effects, and the identity of the actual active constituent(s) may not be known.


• There is a lack of methodology for evaluating herbal products. Research approaches must include the development and validation of methods for determining active, marker and toxic constituents in herbs and herbal products.


• There are difficulties in using “marker compounds” — some are ubiquitous in plants, while others are selected due to the availability of a reference material rather than for a biologically significant reason. In addition, few markers alone are capable of differentiating plant species or sub-species.


• Sophisticated analytical techniques such as GC-MS or HPLC-MS are expensive and may be less useful in complex biological materials, and the use of microscopy and thin-layer chromatography (TLC) are not often used to test raw materials. While HP–TLC is being recognized as an effective technique, validation guidelines are needed.


• Evaluation of herbal preparations needs to include consistency studies, chemical profiling and determination of pharmacological markers to assist and supplement clinical studies.


• Product quality or content may vary substantially depending on factors such as harvest date, storage and processing practices, and mixing of species.


• Analytes of interest may be present at low levels and/or found with a multiplicity of biological materials with varying degrees of pharmacological activity.


• Certified Reference Materials or authenticated botanical materials are generally not obtainable, are difficult to find, or are expensive, and proficiency-testing programs are not commonly available.

Addressing NHP Analytical Quality Issues

The NHP Research Society of Canada (Burnaby, BC) was founded by a collaboration of academic, industry and government researchers from across Canada to support and promote education and scientifically rigorous research on NHPs, including development and validation of analytical methods.

AOAC International (Gaithersburg, MD) has contracted with agencies such as the U.S. Food and Drug Administration and the National Institutes of Health (NIH) to develop fully validated methods for selected NHPs (or dietary supplements, as they are known in the U.S.). An AOAC Task Force on Dietary Supplements has been established to select and evaluate methods to be validated and a call has been issued for analytical methods for high-priority products. Expert review panels will assess methods against the AOAC single laboratory validation criteria as a guide to the suitability of methods for full collaborative studies.

The AOAC Technical Division on Reference Materials (TDRM) is working to determine what role the Technical Division can play to link RMs with validated methods as they are placed in the AOAC e-CAM system.

In Canada, the National Research Council of Canada (Ottawa, ON) has established analytical reference standards production and in the U.S., the National Institute of Standards and Technology has initiated a project to produce SRMs for botanicals. The United States Department of Agriculture has an inter-agency agreement to develop methods and produce SRMs for botanical materials, and the U.S. Pharmacopeia has an active reference materials program.

The Herbal Evaluation and Analysis Laboratory at BCIT (British Columbia Institute of Technology) in Burnaby, B.C. acted as the reference laboratory in a collaborative study to assess the accuracy and reliability of an HPLC method for the five major components of North American ginseng. Additional collaborative studies and proficiency test programs are planned, both to assess methods and to stimulate laboratory capability.

NCCAM (the U.S. National Center for Complementary and Alternative Medicine) policy, while advocating the use of botanical products, requires that companies promoting products that are not well-characterized must provide evidence that materials have been reliably identified. In addition to identifying natural product constituents, products should also be tested for contaminants.

The U.S. NIH Office of Dietary Supplements seeks to allocate funds to speed up collaborative efforts to develop and disseminate validated analytical methods and reference materials for the most commonly used botanicals and other dietary supplements.

Basic Quality System Components
Companies new to the NHP industry, or unfamiliar with the analytical and other procedures and processes involved in meeting the new NHPD Quality Assurance and GMP requirements, may have limited experience in performing and documenting the complex analyses that are required. While accreditation to ISO 17025 should be the ultimate goal for an analytical testing laboratory, including meeting all of the results and method validation, documentation and document control requirements, in-house and contract laboratories may start by developing or building a basic quality system.
Key components of a basic laboratory quality system include the following:
Laboratory uses validated methods

Ideally, collaboratively studied methods should be available, but often laboratories must use in-house validated methods or methods that have been validated by only a few laboratories.

Laboratory has method/results validation data

This may include a standard curve demonstrating linearity, demonstrating acceptable reproducibility and precision through use of replicates, determination of detection limits, use of standards to demonstrate accuracy, use of positive and negative controls, successful participation in proficiency tests, generating spike recovery data, and procedures to estimate measurement uncertainty.

Use of verified reference standards

A basic requirement is that the laboratory uses standards when required; this should involve reference standards when they are available, or at least validated in-house standards. It’s also necessary that laboratories confirm the identity and purity of standards that they purchase and that standards are stored appropriately.

Use of Standard Operating Procedures

SOPs are authorized written procedures that give instructions for performing various laboratory operations and procedures. A few examples include instructions for the calibration and proper use of equipment, receiving and handling samples, cleaning glassware, interacting with clients and handling complaints, and reporting results. Key management requirements are that written SOPs are followed, that there be a standard format for writing SOPs, and that the laboratory has an up-to-date list of SOPs.

Maintaining technical and analytical records

Records must be readily retrievable and traceable, and records of original observations and calculations must be kept and be traceable to the samples tested. Laboratories must also have acceptance and rejection criteria for results.

Maintaining records for technical staff

These include records of educational and professional qualifications, training and skills records, relevant authorizations and documenting familiarity with the quality system.

Identification of a person responsible for the quality program

It is important that laboratories appoint a quality manager or quality assurance officer, reporting to senior management, who is responsible for developing and maintaining the laboratory quality system. For small laboratories this may be a part-time position, or this person may have additional responsibilities.

Participation in relevant proficiency testing (PT) programs

Participation in PT programs is a valuable way to provide an objective assessment of laboratory capability, and of course this must involve acceptable performance.

Procedures are in place for recording and handling complaints

It is important to define procedures to address complaints, respond appropriately including corrective actions and developing preventive actions, and then maintaining records of these actions.

Test reports contain required information

In addition to the basic laboratory and client information, the test results must be clearly stated and the report must have the signature of the person authorizing the test report. It is also wise to include a statement indicating that the results relate only to items tested.
Management review procedures

While the QA manager is responsible for the ongoing operation of the laboratory quality system including internal audits, the senior manager must at least annually chair a comprehensive review determining whether the laboratory is “doing the right things and doing things right.” This includes confirming the laboratory quality policy statement, assessing changes in volume and type of work, reviewing client feedback, identifying and acting on complaints via corrective and preventive actions, reviewing results of proficiency tests and receiving reports from staff.

A checklist composed of these issues, as part of an internal audit, may be used to establish whether all of these components exist and are being followed in the laboratory. It is recognized, of course, that while quality system issues relating to competence and accreditation are key factors in selecting a test laboratory, other selection criteria must include price, availability, laboratory technology and communication systems and practices.

Jerry Hirsch, PhD is director of JH TechRight Consulting Services (Abbotsford, BC), providing advice on quality systems, accreditation to ISO 17025 and natural health products. He previously worked for the Canadian Food Inspection Agency (CFIA) food laboratory and the Health Canada Food/Drug laboratory in Burnaby, B.C. Hirsch is a member of AOAC International and a member of the BC Functional Food & Nutraceutical Network (Vancouver, BC) Natural Health Products Analytical Division.