Time to Replace PHOs? FDA Proposes to Remove Added Trans Fats from Processed Foods

By EAS Senior Advisor for Food and Color Additive Safety Robert Martin, Ph.D.

Partially hydrogenated oils (PHOs) have been in the news a lot recently. Since the 1990s, a strong association of PHOs (which contain trans fat) with harmful effects on human health, especially on blood cholesterol levels and the risk of cardiovascular disease, has been established. This has caused food manufacturers to take steps to reduce the amounts of PHOs in foods. PHOs are the main source of added trans fat to the diet, which is the focus of all of the safety concerns. Since 2006, FDA has required that added trans fat be listed on the nutrition facts panel. While the amount of added trans fat has been reduced significantly – currently, the consumer consumes approximately 1 – 1.3 grams of added trans fat per day (See bit.ly/1cbakrT) as compared to 4.6 grams per day in 2003 (78 FR 67171; November 8, 2013). Notwithstanding this reduction, FDA believes that given the safety concerns associated with the use of added trans fats, the amounts should be significantly lower. Because of these concerns, in a November 8, 2013 Federal Register notice (78 FR 67169 – 67175), FDA announced that it has tentatively determined that partially hydrogenated oils, the primary dietary source of artificial trans fat, are no longer generally recognized as safe (GRAS) for any use in food and that PHOs are therefore food additives subject to section 409 of the Federal Food, Drug, and Cosmetic Act. If finalized, this finding will mean that food manufacturers could no longer add PHOs, either directly or as ingredients in another food product, without prior FDA approval for use as a food additive. To demonstrate that the use of trans fat under the food additive regulation is safe could prove to be a difficult hurdle.

The agency said it based its new determination on current scientific evidence including the opinions of expert panels and the 2005 recommendation of the Institute of Medicine (IOM) that consumers should limit their trans fat consumption as much as possible while consuming a nutritionally adequate diet. According to the Centers for Disease Control and Prevention, elimination of PHOs from the food supply could prevent 10,000 to 20,000 coronary events and 3,000 to 7,000 coronary deaths annually, if the marginal benefits of continuing to remove trans fats from food items remain constant.

“Given this evidence, we have tentatively determined that there is no longer a consensus among qualified scientific experts that PHOs, the primary dietary source of industrially-produced trans fatty acids, are safe for human consumption, either directly or as ingredients in other food products,” FDA said.

The agency’s latest move takes place in the context of a decline in the use of trans fats. In 2010, FDA prepared an estimate of the intake of industrially-produced trans fat using available food consumption data (2003–2006 National Health and Nutrition Examination Survey (NHANES)), market share information, and trans fat levels based on label declaration data and analytical data for products that were identified as containing PHOs. According to that estimate, the mean dietary intake of industrially-produced trans fat has decreased significantly since the previous estimated a decade ago.

The agency has invited comments on the tentative determination by January 7, 2014.

Many manufacturers have taken steps to reformulate their products to remove and/or eliminate added trans fats, but the process is incomplete. It appears likely that FDA will require labeling of any added trans fat and not the current labeling which requires the amount to be stated only if it exceeds 0.5 grams per serving [21 CFR 101.9(c)(2)(ii)]. It is possible that FDA will set a Daily Reference Value (DRV) for added trans fats.

Among the alternatives that manufacturers may consider would be the use of interesterified oils (where the structure of the oil is enzymatically or chemically modified to make them more solid or stable), or using blends of oils to achieve the desired effects, or using butter (which contains natural trans fat), or developing new products that could achieve the desired oil/fat properties, etc. All of these approaches have their pluses and minuses. For example, new oils may remove the trans fat issues, but could raise formulation, taste and regulatory issues that will need to be resolved.

A large number of products on the market still use PHOs, so reformulating these products will be an ongoing process. The EAS consulting network can provide expertise in nutrition, labeling, regulatory and related areas to help meet the challenges of product reformulation.

FDA Needs Input on Proposed Animal Food Rule

In last month’s FSMA Perspective, I focused on FDA’s release of its proposed rule on Current Good Manufacturing Practice (CGMP) and Hazard Analysis and Risk-Based Preventive Controls for Food for Animals. I would like to follow up here with issues raised November 21 at a public meeting in College Park, MD — the first of three FDA meetings on the animal feed proposal. The agency held a second session in Chicago, IL, Nov. 25, and has scheduled a third for Sacramento, CA, on December 6.

These meetings are extremely helpful for two-way communication between the agency and stakeholders. The regulated industry learns the agency’s thinking about the proposed rule and FDA staff hears the specific concerns of the stakeholders. I know the agency values these “listening” sessions highly. The first meeting featured public comment and Q&A sessions with senior FDA officials, including: Linda Tollefson, Associate Commissioner in the Office of Foods and Veterinary Medicine; Dan McChesney, director of the Office of Surveillance and Compliance in the Center for Veterinary Medicine (CVM); Kim Young, deputy director of the Division of Compliance in CVM; Eric Nelson, director of the Division of Compliance in CVM; and Jenny Scott, senior advisor in the Office of Food Safety in FDA”s Center for Food safety and Applied Nutrition (CFSAN).

Representatives of the American Feed Industry Association (AFIA) turned out in strength for the first meeting and argued that FDA is proposing to apply tougher preventive controls to animal feed producers than are justified by a risk-based approach. The industry group believes the agency is being overzealous in applying the same rigorous controls to animal feed as it plans for pet foods and for human foods. Instead, the feed industry would like the agency to modify the proposed rule to recognize differences between animal feed and pet food production facilities. The group argues that lawmakers kept animal food separate from human food in FSMA and that the agency needs to do the same. In addition, it wants FDA to apply the same approach to the Federal Food Drug and Cosmetic Act and to separate animal food and human food.

As a former CVM director who is now a consultant to the industry, I can see both sides of this picture. Cleary, there are significant differences between feed mills and pet food processing facilities and these should be taken into account in a final rule. But that does not mean animal feed facilities should get a pass from compliance with FSMA’s preventive approach.

The preventive controls provisions of the proposed rule, would apply to domestic and imported animal food, including pet food, animal feed, and raw materials and ingredients. Facilities producing animal food would be required to have written plans that identify hazards, specify the steps that will be put in place to minimize or prevent those hazards, identify monitoring procedures and record monitoring results, and specify what actions would be taken to correct problems that arise. The proposed rule would also establish CGMPs that specifically address animal food. This will be a burden for the feed industry, which will have to comply with CGMP requirements for the first time.

The clock is ticking down toward the court-ordered deadline of June 30, 2015 for publishing this and four other FSMA final rules. So this does not leave much room for additional rounds of comment beyond the current comment deadline of February 26, 2014. For this reason — as I have suggested here before — now is the time for the regulated industry to play an active role in this rulemaking process.

On FDA’s Proposed Rule on Preventive Controls for Animal Food Facilities

FDA unveiled its proposed rule on Current Good Manufacturing Practice and Hazard Analysis and Risk-Based Preventive Controls for Food for Animals on October 25 after more than a year and half of waiting for the proposal to emerge from the White House Office of Management and Budget.

This proposed rule is of particular interest to me — as a veterinarian and a former director of FDA’s Center for Veterinary Medicine –and I think it has the potential to make a significant impact on animal health and to improve the safety of the human food supply.

The rule represents the biggest regulatory change the animal feed industry has seen in decades, with many companies becoming subject to new Current Good Manufacturing Practice (CGMP) requirements as well as hazard analysis and preventive controls for the first time. However, there will be added costs for companies required to comply with the new CGMPs and to develop preventive controls. With some exceptions, the proposed rule would apply to facilities that manufacture, process, pack, or hold animal food and are required to register as a food facility. So this will include a large number of companies.

Each facility would be required to have a written food safety plan, including a hazard analysis for each type of animal food manufactured, processed, packed, or held at the facility. The plan would also require preventive controls, monitoring procedures, corrective actions, verification activities and recordkeeping — all terms that are familiar to those of you who have worked with Hazard Analysis and Critical Control Point (HACCP) systems, although the term HACCP is not used in the proposed rule.

The animal food rule will complement FDA’s separate proposed rules on imported foods and on the accreditation of third party auditors for foreign food facilities.

I am often asked if I think the agency will be able to meet its new court-ordered deadline of June 30, 2015 for publishing all five FSMA-related final rules. Because of the complexity of the animal feed proposal and of the other four rules, and because some of the necessary elements are beyond FDA’s control, I believe the agency will find it a major challenge to achieve the deadline. It is always a challenge to develop a new rule that must be properly supported by science and that must address the concerns of all stakeholders. So it would be unfortunate to have to rush through any of the necessary steps in the process.

The proposed animal foods rule, formally released in the October 29 Federal Register, is open for comment through February 26, 2014 and FDA has also scheduled several public meetings, one in College Park, MD on November 21, another in Chicago, IL, on November 25, and a third in Sacramento, CA, on December 6. I would encourage companies in the animal food industry to play an active role in this process because FDA is open to constructive comment on the proposal.

A Look at FDA’s Food Contact Notification Program

By EAS Senior Consultant Thomas Dunn

A food additive is defined in Section 201(s) of the Food, Drug & Cosmetic Act (FD&C Act) as any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristic of any food (including any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food; and including any source of radiation intended for any such use); if such substance is not GRAS or sanctioned prior to 1958 or otherwise excluded from the definition of food additives.

For regulatory purposes, FDA divides food additives into two main categories: direct and indirect. Indirect food additives are food additives that come into contact with food as part of packaging, holding, or processing, but are not intended to be added directly to, become a component, or have a technical effect in or on the food. Indirect food additives mentioned in Title 21 of the U.S. Code of Federal Regulations (21 CFR) used in food-contact articles, include adhesives and components of coatings (Part 175), paper and paperboard components (Part 176), polymers (Part 177), and adjuvants and production aids (Part 178). Prior to 1997, all food additives, direct and indirect, were subject to approval via a petition process.

Section 409 of the FD&C Act defines a Food Contact Substance (FCS) as any substance that is intended for use as a component of materials used in manufacturing, packing, packaging, transporting, or holding food if such use of the substance is not intended to have any technical effect in such food. Examples of food contact substances include polymers (plastic packaging materials), pigments and antioxidants used in polymers, can coatings, adhesives, materials used during the manufacture of paper and paperboard, slimicides and biocides (antimicrobial agents), and sealants for lids and caps.

In 1997, the Food and Drug Administration Modernization Act (FDAMA) amended Section 409 of the FD&C Act establishing a “Food Contact Notification” (FCN) process that allows for alternative review of FCSs. The FCN process, administered by the Center for Food Safety and Nutrition (CFSAN), differs from the older food additive petition process in many ways. Most significant is the new program’s scientific approach to managing risk. With no sacrifice to public visibility or information access, the FDA has established specific process guidelines proactively detailing objective data requirements for manufacturing, chemistry, toxicology, and environmental aspects of the production and use of the proposed FCS that applicants must provide. When the applicant has provided FDA with all of the necessary data (the data requirements are described in guidelines published by FDA and are available on FDA’s website), the agency has a 120-day review period to evaluate the safety of the food contact substance as proposed. If there are no identified concerns, the FCN automatically becomes effective on the 120th day. Unlike approved food additive petitions where a regulation is entered into title 21 CFR, the FCN is then added to an Inventory of Effective Premarket Notifications for Food Contact Substances that is posted on CFSAN’s web page.

It is important to note that a food contact notification (FCN) is only effective for the manufacturer or supplier identified in the notification. Anyone who markets a food contact substance (FCS) based on an effective notification must be able to demonstrate that the notification is effective for their food contact substance. All persons who purchase a food contact substance manufactured or supplied by a manufacturer or supplier identified in an effective notification may rely on that notification to legally market or use the food contact substance for the use that is the subject of the notification, consistent with any limitations in the notification

FDA suggests that an FCN applicant discuss the proposal with agency scientists early in the application process. This allows the applicant and agency scientists to discuss the critical data requirements, test protocols, and validation procedures before either dedicates resources to activities potentially inadequate to support FDA’s assessment of public health risk posed by the FCS. Months of chemical and toxicological testing may well precede the 120 day FDA review.

In more than 14 years of existence, the FCN program has processed and listed almost 1,300 substances. The listing includes the FCS, the supplier’s name, the manufacturer of the FCS, the intended use, the limitations on the conditions of use for the FCS and its specifications, the effective date, and FDAs environmental decision. Successful completion of all the data requirements for complete submission involves a thorough understanding of FDA’s administrative process and the data needs of the agency’s scientific risk assessment.

EAS Consulting Group can assist you in preparing and submitting FCNs to FDA. EAS has a large group of professionals on its staff with years of previous experience working for FDA and other government agencies and industries. Please feel free to contact us to discuss your needs and our services.

Reporting from Proposed FSMA-related Audits Raises Concerns

Reporting requirements from third-party audits drew many questions from stakeholders at the agency’s public meeting on proposed rules on Foreign Supplier Verification Programs (FSVP) and the Accreditation of Third-Party Auditors/Certification Bodies, held in Washington D.C., September 19-20.

As you may know, the objective of the accreditation proposal is to strengthen foreign food safety audits – although the agency has indicated that it would consider a similar approach for third-party audits conducted in the United States.

The accreditation rule calls for reports to be submitted to FDA on conditions found in an audited facility that might lead to a serious risk to health. Participants in the public meeting sought assurances from the FDA officials — including Deputy Commissioner for Foods and Veterinary Medicine, Mike Taylor –that this would only be a requirement for a regulatory audit, and not for a purely consultative audit conducted for the purposes of assessing compliance ahead of time. If FDA requires reports from consultative audits, it could cause companies to avoid this type of audit entirely, with the unintended consequence of reducing the number of audits conducted, stakeholders warned. Or, if FDA-accredited auditors had to report findings from consultative as well as regulatory audits, it would encourage companies to seek consultative audits from non-accredited firms. So there are many possibilities for unintended consequences.

Taylor assured participants at the public meeting that the agency wants to be very clear about reporting requirements and when they will and won’t be required. It doesn’t, for example, want to drive companies away from using FDA-accredited auditors in order to protect themselves from reporting requirements, he said.

Consumer groups are concerned that the agency may extend the third-party accreditation program beyond its intended application to imported food and they point out that this was specifically excluded during the deliberations by lawmakers leading to the enactment of FSMA. They view regulatory audits as the domain of the regulatory authorities and not the business of private auditing firms. This policy issue has been debated for many years – and not just with regard to FDA.

Interestingly, the requirement for inspections conducted by certified third-party auditors is limited to only two situations:

  • Imported food determined to pose a safety risk and requiring certification by FDA as a condition of granting admission into the U.S.
  • Issuing foreign facility certifications that will be used by importers to establish eligibility for the Voluntary Qualified Importer Program.

Importers who rely upon third party audits as part of their Foreign Supplier Verification Program are not required to use accredited third party auditors. However, FDA believes that there will be much broader adoption by the food industry of third-party audits performed by auditors certified by FDA-recognized accreditation bodies.

It seems to me that an effective policy must take account of what is possible in practical terms. By this measure, a preventive approach using third-party audits is the only viable option and it is preferable to the alternative, which is likely to be paralysis and no improvement in food safety measures for imported food.


Distinguishing Medical Device Recalls

By EAS Senior Consultant Paul F. Tilton

Do you know when a product enhancement is considered to be a recall in the eyes of the Food and Drug Administration? If not, I draw your attention to the draft guidance from FDA entitled Distinguishing Medical Device Recalls from Product Enhancements and Associated Reporting Requirements. Using plain language and a flow chart, the Guidance offers FDA’s perspective on the differences between the two. It was distributed for comment on February 22, 2013. The comment period ended in May, and FDA is now considering the comments received. I recommend that firms consider this guidance and seek consultation if necessary before making any changes in device design, labeling or manufacturing processes.

I speak with some experience. For twelve years I was a chief of the Ob/Gyn, Gastroenterology and Urology Branch, in the Division of Enforcement, Office of Compliance (OC), Center for Devices and Radiological Health (CDRH). Prior to my retirement in early 2012, certain steps taken by my branch in coordination with others in CDRH were instrumental in the genesis of this document. Let me explain. We became aware that a manufacturer had proposed a design change in a marketed device via the Premarket Approval (PMA) supplement process. Concurrently, we noted that several adverse events involving the same device had been reported through the Medical Device Reporting (MDR) system. Was there a connection?

After in-house (i.e., CDRH and the FDA district office) discussion, we opened dialogue with the manufacturer and shared points of view. The firm acknowledged the original design of the device might have been a contributing factor to the injuries reported via the MDR process, but concluded, nevertheless, that the design change was a product enhancement and a recall was not warranted. We expressed the need for a voluntary recall because of the seriousness of the health hazard, the likelihood of recurrence and other aspects.

This was not a unique situation. Quite often we encountered similar situations requiring meetings with manufacturers to clarify expectations. In this case, as always, we worked closely with the recall coordinator in the FDA district office and engaged the manufacturer only after having an FDA Health Risk Assessment in hand and the support of experts from OC, the Office of Device Evaluation (ODE), the Office of Surveillance and Biometrics (OSB) and others.

In the above situation, the Center’s point of view prevailed, and the manufacturer agreed to conduct a voluntary recall. Once that matter was settled, the firm asked to meet with us to get a better understanding of FDA’s processes to avoid similar problems in the future. We welcomed this discussion and recognized the need for a Guidance document.

The Guidance includes: 1) definitions of terms, 2) identification of what a recall is and isn’t, 3) clarification of violative and non-violative devices, 4) a recall decision making flow chart, 5) recall reporting requirements, and 6) product enhancement reporting requirements. It also discusses associated regulations, including 21 CFR 803 (Medical Device Reporting) and 21 CFR 806 (Reports of Corrections and Removals). A Q&A format is used throughout.

The Guidance is still in draft form and may change somewhat to reflect the comments received. But for now it is of value for helping to understand FDA’s perspective on device recalls versus product enhancements.

Regulatory Options for Food Ingredients in the U.S.

By EAS Senior Advisor for Food & Color Additive Safety Robert Martin

Before releasing any food ingredient into the market, it is incumbent upon the manufacturer/supplier to ensure that the product is safe for its intended use. Oftentimes, deciding how to approach this can be confusing. Under the Federal Food, Drug, and Cosmetic Act, the manufacturer/supplier has primary responsibility for ensuring that a food ingredient is safe, and FDA has the primary legal responsibility for determining that the ingredient is safe under its intended conditions of use. Since 1958, manufacturers have had several options for determining that an ingredient is safe for use in food. These options are listed in the Table below.

Table I: FDA Recognized Approaches to Food Ingredients

Regulatory Option Regulatory Citation Comments
Food Additive Petitions Direct food additive Secondary direct food additive Indirect food additive 21 CFR 171.1 Today used mainly for direct food additives; most indirect food additives use the FCN route if they qualify; some secondary direct additives may also qualify for the FCN route.
Color Additive Petition 21 CFR 71.1 Required for colors
GRAS Petitions 21 CFR 170.35 May be direct or indirect additive; superseded by GRAS Notice program
GRAS Notice See 62 FR 18938ff; April 17, 1997 Voluntary; in practice since 1997; FDA has received more than 400 GRAS Notices since the inception of this program.
Independent GRAS Determination Section 201(s) of the FD&C Act An option; before undertaking, we suggest discussing this option with EAS.
Threshold of Regulation 21 CFR 170.39 Restricted to indirect additives
Food Contact Notification 21 CFR 170.100 This route is now the main route for seeking approval of indirect additives.
New Dietary Ingredient 21 CFR part 190 In effect since 1994; the Dietary Supplement Health and Education Act (DSHEA) amended the FD&C Act to distinguish dietary ingredients as a special case of food ingredients. Prior to 1994, dietary ingredients were treated as other food ingredients.

In effect since 1994; the Dietary Supplement Health and Education Act (DSHEA) amended the FD&C Act to distinguish dietary ingredients as a special case of food ingredients. Prior to 1994, dietary ingredients were treated as other food ingredients.

Food additives can be classified into four main groups: 1) food additives; 2) color additives; 3) ingredients for which either the FDA or the U. S. Department of Agriculture specifically authorized use prior to 1958, the so-called “Prior Sanctioned Substances”; and, 4) GRAS substances, i.e., substances that are agreed upon as safe by the general scientific community on the basis of scientific evidence or history of use prior to 1958. Only food and color additives require premarket approval.

The manufacturer/supplier should first decide which regulatory options meet the intended use. FDA has issued definitions for these food ingredients to assist in this decision. The definitions below are taken from FDA’s Food Ingredients and Packaging Terms.

Direct food additives are those added to a food for a specific purpose in that food.

Color additives may be any dye, pigment or substance which when added or applied to a food, drug, or cosmetic, or to the human body, is capable (alone or through reactions with other substances) of imparting colors.

GRAS (Generally Recognized as Safe) ingredients are those ingredients that are generally recognized by experts to be safe, based on either an extensive history of use in food prior to 1958, or based on published scientific evidence. The determination that a substance is GRAS is not exclusive to FDA. Scientists outside FDA may also make this determination based on the available evidence. However, manufacturers/suppliers may request that FDA review their determination by submitting a GRAS Notification to FDA for review and concurrence. After completion of its review, if FDA concurs, the agency will issue a “No Questions” letter to the submitter indicating that “FDA has no questions at this time …” regarding the GRAS determination.

Any ingredient used in food is expected to be produced and used consistent with Good Manufacturing Practice (GMP) conditions to ensure its safe use. The responsibility for establishing GMP conditions rests primarily with the manufacturer/supplier. Once in use, it is important that the manufacturer/supplier continue to monitor the use of the product to ensure its use continues to be within safe limits.

FDA has also issued several guidance documents to assist manufacturers/suppliers in their effort to seek approval of their food ingredient(s). These guidance documents are posted on the agency’s website.

Should a manufacturer/supplier wish to add an unregulated ingredient to food, we invite them to contact EAS. EAS has a large network of expert scientists with many different areas of expertise and regulatory experience. Among these are food scientists, chemists, toxicologists, and regulatory experts. For specific expertise not available within the EAS network, we also maintain contact with a large number of outside experts to assist on any project.

On the Proposed Rules for the Safety of Imported Food

One of FDA’s biggest challenges as it rolls out new regulations to implement the Food Safety Modernization Act will be outreach and education so every impacted business will know what’s expected under the new, prevention-based regulatory approach. As part of its outreach efforts, FDA posted a presentation on its website on August 19, titled Proposed Rules to Help Ensure the Safety of Imported Food, in which it describes the elements of the Proposed Regulations for Foreign Supplier Verification Programs (FSVPs) and the Proposed Rule for Accreditation of Third-Party Auditors.

The agency explains that the new, integrated approach to imports will include the FSVP and the voluntary qualified importer program (VQIP). But it will also include mandatory certification, and enhancements to the existing prior notice system. In addition, the agency wants to help build the capacity of foreign governments, and to expand its own foreign offices. And it has other tools at its disposal, such as stronger enforcement authority under FSMA.

As you may know, a key principle of the import-related rules under FSMA is that the importers will be responsible for ensuring that the food they import to the U.S. complies with FDA safety standards. Unless a product has a specific exemption, the importer will be required to develop an FSVP for each food imported, with varying requirements based on the type of product, the category of importer, the hazard of the specific food, and on who will control the hazard. If there is no U.S. owner of the food at the time of entry, the importer is deemed to be the U.S. consignee. And if there is no consignee or U.S. owner at the time of entry, the importer will be the U.S. agent or representative of the foreign owner or consignee.

The proposed requirements for supplier verification are mainly based on who will control the hazards that are reasonably likely to occur.

The agency is attempting to be fair with regard to exemptions and to avoid duplication of effort by companies already covered by other preventive requirements. So, for example, products from facilities subject to FDA’s low acid canned food requirements will be exempt, but only with regard to the microbiological hazards elements of the rule. In addition, the agency proposes modified FSVP requirement for dietary supplements and for dietary supplement components.

For these and for other reasons, I believe the FSVP will be a complex regulation to implement, with many opportunities for confusion of responsibilities and roles. As a former regulator, I have sympathy with the agency as it gets deep into this huge task that will take many years to complete. I encourage you to speak up if you see elements of the proposed rules that will be unduly burdensome and to present FDA with workable regulatory solutions. Now is the opportune time.

ISO/IEC 17025:2005 and the Benefits of Accreditation

By EAS Senior Consultant Bob Mehta

There is immense value for medical device manufacturers in having their calibration and testing laboratory suppliers comply with the General Requirements for the Competence of Testing and Calibration Laboratories in ISO/IEC 17025:2005.

From initial design and development to the shipment of medical devices that can be characterized as safe and effective, the accuracy of the testing and inspection results depends on the use of measuring and monitoring equipment that is calibrated. In addition, the materials used in the manufacture of medical devices need to be tested to ensure the materials are appropriate. Design and process validation activities, the assessment of material biocompatibility, packaging studies, sterilization validation and electrical performance testing must be performed to a high-degree of reliability.

The FDA demands that these activities are performed using monitoring and measuring equipment with a high-degree of accuracy. The only way to ensure that the integrity of the testing results is through the use of an accredited ISO/IEC 17025 facility for calibration and testing.

Other Industries

Other regulated industries such as dietary supplements (21 CFR, Part 111), pharmaceuticals (21 CFR, Part 211), Medical Devices (21 CFR 820) and even aerospace (AS9100 – premised on ISO 9001), rely on the integrity of testing and need to employ monitoring and measuring equipment that is accurately calibrated with traceability to a national standard, for example to National Institute of Standards and Technology (NIST) or other recognizable standards. Pharmaceuticals and dietary supplements, similar to medical devices, must be safe and effective in their intended use. These industries also employ extensive verification and validation testing and subsequent inspection to ensure product safety.

Reasons for Compliance

In 2005, Hershal C. Brewer explored the reasons for the use of ISO/IEC 17025-accredited suppliers for calibration and testing. In Quality Digest Magazine, Brewer listed the following reasons:

  • Product testing to verify suitability of product for market introduction;
  • Compliance with regulatory and statutory requirements;
  • Ensure product safety and efficacy;
  • Achieve product certification from organizations such as Intertek or UL; and
  • Regulatory requirement to achieve product listing.

The need for medical device manufacturers to calibrate equipment is a fundamental requirement mandated by 21 CFR Part 111 (Subpart D – Equipment and Utensils § 111.35), 21 CFR 211 (Subpart D – Equipment Section 211.68 and Subpart I – Laboratory Controls Section 211.160), 21 CFR Part 820 (Section 820.72 Inspection, measuring, and test equipment) and enforced by FDA during their inspections of device manufacturers. A similar requirement is mandated by ISO 9001:2008/ISO 13485:2003 and AS9100 Rev. C under Clause 7.6 (Control of measuring and monitoring devices). Considering the regulatory oversight provided by FDA in the United States, and the notified bodies in support of ensuring compliance to 93/42/EEC (the Medical Device Directive); selecting a metrology supplier that is ISO/IEC 17025 accredited is the prudent path to pursue. If the device manufacturer is performing calibration activities in-house, then complying with ISO/IEC 17025 would be considered a best practice.

For the execution of testing activities, selecting qualified testing laboratories is not considered optional by the FDA. Regulatory bodies expect testing to be performed by qualified laboratories. Additionally, a qualified testing laboratory is expected to be ISO/IEC 17025 accredited. For example, if testing is being performed to IEC 60601-1 (Medical electrical equipment – Part 1: General requirements for basic safety and essential performance) the expectation is that testing be performed at an accredited testing facility such as Intertek. Asking FDA to accept test data from an unaccredited testing facility will not draw a favorable response.

In conclusion, the rigorous standards for medical devices require them to be designed, developed, validated, and manufactured to be safe and effective for their intended use. Obtaining testing and inspection results through the use of calibrated equipment is a fundamental requirement enforced by FDA and other regulatory bodies. For accurate results, the prudent path is to select and qualify calibration and testing facilities that are ISO/IEC 17025 accredited. If the calibration and testing is being performed in-house by a manufacturer, compliance with ISO/IEC 17025 would be considered a best practice. But regardless of the approach pursued for testing and calibration, in-house versus supplier, ISO/IEC 17025 must be considered.

FSMA’s Registration Mandate is the Key

The focus of media attention is currently on FDA’s proposed rules for a Foreign Supplier Verification Program and for Accreditation of Third-Party Auditors. But I would draw your attention to a FSMA provision that is already in force, which, from the agency’s viewpoint, is the most significant new authority under the new law — biennial registration of facilities.

The true significance of the registration mandate is, I believe, being overlooked in the media because of the focus on proposed rules and delays. Under FSMA, facilities that manufacture, process, pack, or hold food for human or animal consumption in the United States must register with the agency every two years. There are some exemptions, namely farms, retail food establishments, restaurants, non-profit food establishments, and fishing vessels. But the mandatory registration requirement means that a large number of companies that were not previously very visible to the agency will now be on the radar screen.

Prior to the Bioterrorism Act of 2002, food manufacturers were not required to register with FDA so the agency had to do the best job it could to compile an inventory of food manufacturers so they could be inspected on a regular basis. This was supposed to occur at least once every five years. FDA relied on the states to identify food firms in their state based on tax records and other state requirements for licensing and registration. But this information was often inaccurate or incomplete. Compiling a list of foreign food firms that imported to the U.S. was even more problematic.

On several occasions, outbreaks of foodborne illness were traced to firms that had never been inspected by FDA either because they were considered low on FDA’s priority list or because they were not in FDA’s inventory.

The Bioterrorism Act required all food manufacturers foreign and domestic to register with the FDA thus solving the inventory problem. But the amount of information required by the law was very limited so that FDA often could not tell whether the firm was producing low-risk or high-risk foods. The greatest limitation to the Bioterrorism Act was that companies were only required to register one time. Companies were required to update their registration information if they made changes in the foods they produced and other changes, but many neglected to inform FDA. A 2009 Inspector General’s report indicated that 48 percent of registered facilities gave inaccurate information or failed to update information. Over time the inventory became less and less accurate, which contributed to the disaster that was the Peanut Corporation of America.

PCA’s Blakely, GA plant was registered with FDA as a roaster and blancher of peanuts which was considered fairly low-risk by FDA. By the time of the massive Salmonella outbreak beginning in late 2008, the plant was producing a variety of peanut products including peanut paste. These peanut products were sold to other food companies throughout the U.S. including large companies like Kellogg. When FDA traced the source of the outbreak to the PCA Blakely plant in early 2009, I believe all of the prior inspections were conducted by Georgia state officials under FDA contract. At $500 per inspection under the FDA contract, Georgia inspectors could not do a thorough job and missed many GMP violations that contributed to the establishment and spread of Salmonella throughout the plant. Had PCA bothered to update its registration to reflect its expanded product line, the FDA may have targeted the Blakely plant for an inspection ($10,000 is the cost of an FDA inspection) and prevented the outbreak.

Under FSMA, food facilities are required to reregister every other year and list any changes to the food categories they produce. Furthermore FSMA gives FDA authority to suspend registration if facilities do not comply with the registration requirements. Overall this gives FDA much greater control of its food facility inventory, increases its ability to target high-risk firms, and provides regulatory teeth to encourage compliance.


Botanical Drugs: What Might the Future Hold?

By EAS Senior Consultant Brad Douglass

The Food and Drug Administration’s recent approval of Fulyzaq (crofelemer), an anti-diarrheal drug for HIV/AIDS patients, was a first for an oral, prescription botanical drug. Prior to that approval, the topical preparation Veregen (sinecatechins), a green tea extract used to treat genital warts, was the sole prescription, botanical drug awarded New Drug Application (NDA) approval.

With the experience gained from these two approvals and a number of other botanical Investigational New Drug (IND) applications, the Botanical Review Team (BRT) of the Center for Drug Evaluation and Research (CDER) is developing an updated Botanical Drug Products Guidance for Industry.

A distinct regulatory category for “herbal medicine products” does not exist in the U.S. as it does in Canada and Europe. Instead, a botanical drug product, like all drugs, is defined by the intended use in the diagnosis, cure, mitigation, prevention or treatment of disease in humans. Any dosage form or route of administration available to drugs as a class (liquid, capsule, topical, injection, etc.) is also possible for the subset of botanical drugs.

One characteristic that makes botanical drugs unique is composition. They may consist of vegetable material derived from plants, algae, and macroscopic fungi, but not highly purified or chemically modified substances of botanical origin. Botanical drugs are likely to be complex mixtures that lack a distinct active ingredient or even discernible active components. This can make product consistency and stability more challenging, and is reflected in additional Chemistry, Manufacturing, and Controls (CMC) requirements. 

In addition, prior human use often sets botanical products apart. For this reason, the agency reviews botanical IND applications to determine if existing data can stand in for typical requirements. For example, non-clinical toxicity studies are often waived for botanicals extensively used in traditional systems of medicine or as dietary supplements.

A new guidance document will likely refine the agency’s treatment of a few key areas. These include the means for controlling product consistency and how a product composed of multiple parts of the same plant will be evaluated. 

FDA’s primary concern is the therapeutic consistency of marketed batches of a drug product. But unlike with purified non-botanical drugs, CMC requirements for botanical drugs may not be relied upon solely to control therapeutic consistency. Updates in this area are expected, including refined criteria for analytical fingerprinting and further recommendations for developing clinically relevant bioassays. Clinical dose response data, especially in cases of relatively flat dose response (cf. Veregen) will probably be addressed. Further recommendations for demonstrating negative batch-to-batch treatment effects and for monitoring post-marketing issues are also likely.

The updated guidance may also seek to clarify what constitutes a single ingredient botanical drug product and what constitutes a combination product. To date, FDA has not objected to naturally occurring mixtures of components in a single plant part as constituting a single ingredient. However, using different parts (e.g. root and leaves) of the same plant creates a combination product, as does mixtures of more than one botanical.

Many in the pharmaceutical industry have commented that the existing botanical dietary supplements are a disincentive to rigorous drug development because their existence may negate exclusivity. Meanwhile, many in the dietary supplement industry consider the cost of NDA approval too high.

The cost of botanical drug approval is unlikely to diminish, as the U.S. regulatory framework established for botanical drugs is here to stay. However, this does not necessarily imply that botanical drugs will remain a category that averages 1-2 approvals per decade.

Changing Industry Dynamics

As dietary supplement ingredient manufacturers continue to innovate and develop ever more sophisticated, clinically substantiated products, the cost differential between launching a dietary supplement ingredient and obtaining approval of a botanical drug will decrease. The supplement industry may find that harmonizing ingredient R&D strategies with botanical drug regulatory expectations will provide both a pre-clinical/clinical and a funding runway for botanical drug development.

As the pharmaceutical industry continues to move further into the dietary supplement space, there will be an increasing intermingling of resources and ideas amongst business units. This could revive past natural product discovery paradigms. Some firms may even attempt to use the Orphan Drug and FDA Breakthrough Therapy to facilitate botanical drug approval.

Although an abbreviated new drug application (ANDA) path is possible for botanical drugs, in principle, FDA recognizes that it may be extremely difficult to prove the necessary equivalence amongst two “similar” products to demonstrate that they are pharmacologically identical or therapeutically interchangeable. In practice this may preclude generic botanical drugs.

If dietary supplement manufacturers made comparative claims to botanical drugs, FDA could act to stamp out such illegal disease/treatment claims. This could help diminish one projected threat to exclusivity. And unlike dietary supplements, prescription botanical drugs would be reimbursable under [some] medical insurance plans, helping their competitiveness. 

In summary, the long-term prospects for botanical drugs may be rosier than they currently appear. In fact, firms in the business of producing health products may miss an opportunity if they fail to consider this relatively new regulatory path.