FROM THE 2015 FEED ADDITIVE COMPENDIUM
by Richard Sellers
Richard Sellers is senior vice president of legislative and regulatory affairs for the American Feed Industry Assn., a national trade association representing the interests of nearly 600 feed manufacturers, distributors, ingredient suppliers, equipment manufacturers, nutrition consultants and animal health distributors. He holds a B.S. from the University of Memphis and an M.S. in poultry science from the University of Arkansas.
Medicated feed manufacturers are subject to current good manufacturing practice regulations (CGMPs) and should be aware of the purpose and origin of the term. In understanding such origin and purpose, manufacturers should be better equipped to comply with the provisions of the regulations.
The regulations in general are very specific but open to interpretation about how to comply. Generally, there are few problems resulting from interpretation differences, but medicated feed manufacturers should be aware that differences of opinions can and do occur over the meaning of the regulations. Several differences are discussed below.
Source of Term
The term is found in the Federal Food, Drug & Cosmetic Act, where it is stated that products may be deemed to be adulterated if they are not produced in conformance with “current good manufacturing practices.” Note the word current, which means present or today, not the past or future. Note also that the standard is the conditions under which the product is produced, not the condition of the product itself. Actual adulteration is not necessary. If the conditions of production are less than currently accepted and generally practiced by industry — as described in the CGMP regulations, the product can be deemed adulterated from a regulatory perspective. Hence, compliance with CGMPs is a practical necessity.
Requiring compliance with CGMPs is, in effect, an expression of regulatory philosophy. It is a “before the fact” preventive type approach to the control of medicated feeds. Compliance with CGMPs should insure, to the extent possible, that medicated feeds will be proper in all respects as to drug content and labeling and furthermore, that medicated feed production will not compromise other medicated feeds or non-medicated feeds. Compliance with CGMPs by the medicated feed manufacturer is intended to provide the Food & Drug Administration with reasonable assurance that there is proper use of animal drugs. The alternative is an “after the fact” program of sampling and testing to uncover any problems. Prevention is more efficient and effective.
CGMPs are an industry standard in the format of FDA’s regulations. They are adopted through the rule-making process and have the effect of law.
CGMPs are those practices reflecting available information accepted by the majority of feed manufacturers. CGMPs are neither stagnant nor are they only one person’s opinion. Therefore, these practices will vary depending on a variety of issues, such as drug used, type of equipment, physical facilities and customer served.
Good Business Practices
While specific practices will vary, there are some common threads of good business practice. There is strong reliance on good housekeeping, inventory controls, a meaningful documented history of production tied to responsible individuals and the ability to trace and locate product in the field if necessary — and likewise to trace product back from the field and back through the process of its production if this is necessary. Operation should be on a predetermined, systematic and documented basis.
Industry Input/CGMP Principles
Industry — through the American Feed Industry Assn. — contributed in a significant manner to the original FDA feed CGMP regulations implementing the CGMP provision of the law and had substantial input into the current version. This contribution was appropriate since AFIA’s feed manufacturing members are the professionals in this regard who hold the expertise on good manufacturing practices. The current version of the CGMP regulations mirrors the principles set forth in the first set of regulations. Prominent in those principles is the fact the CGMP regulations provide a high degree of flexibility in achieving specific end points. In effect, objectives are specified and means to achieve them outlined, with flexibility provided on how to meet these objectives. This is a departure from the norm. Usually regulations are rather specific rules implementing provisions of law. The difference with the CGMP regulations is directly related to the wide variety of feed manufacturing/mixing facilities and products and the need for flexibility in determining and applying CGMPs. Flexibility is also needed to keep current, since current means a moving target as time passes. The increasing use of computerized controls and records is an example of change that must be accommodated by the regulations.
The objective of the CGMP provision in the law is to require adherence to a current general standard of manufacturing which will promote products that meet intended specifications. Put another way, that the practices employed — including controls — can be expected to result in medicated feed products containing the correct drug at the intended level with proper labeling. Furthermore, that the integrity of the product is maintained, as is the integrity of other products produced in the same facility.
Licensed vs. Non-Licensed CGMPs
The first portion of the regulations, Sections 225.1 through 225.115, applicable to federally licensed mills, consists of a series of two part subsections — parts (a) and (b). Part (a) basically is an expression of philosophy and objectives while part (b) gives a “how to” explanation. The second portion, Sections 225.120 through 225.202, consists of a series of single paragraphs which are expressions of philosophy and objectives paralleling their counterpart subsection (a) of the first portion for licensed mills. With respect to how to comply, non-licensed mills must simply find the best means of achieving the objectives embodied in the expressions of philosophy.
Licensed facilities are subject to routine inspection by or for FDA once every two years for compliance with CGMPs. Non-licensed facilities are not subject to routine FDA inspection. All mills are subject to inspection “for cause,” such as association with adulterated or misbranded feed or food product with illegal drug residues.
FDA issues a CGMP inspection guide periodically. This guide is issued to FDA’s district offices as a “Compliance Program Guidance Manual Compliance Program: 7371.004 — Feed Manufacturing Compliance Program (updated periodically).” It may be requested from FDA or its district offices or found at www.fda.gov/AnimalVeterinary (search for the guide by name) and should be reviewed by all feed industry personnel involved in feed regulatory compliance. This guidance manual incorporates inspections for VFD, BSE feed rule and medicated feed. The manual has been updated by FDA for reissuance but does not contain the FDA Form 2481 or medicated feed mill inspection form.
The guide differentiates inspections into surveillance and compliance inspections. Surveillance inspections are those routine, biennial inspections required of all medicated feed mill license holders. Comprehensive inspections are an in-depth review of a mill’s compliance to CGMPs and normally result when a problem is suspected, previously noted or is apparent.
Feed Producer Action
Every feed manufacturer-mixer of medicated feeds must review the portion of CGMP regulations applicable to their operation, determine what constitutes good manufacturing practices for the operation and insure that the practices and procedures followed comply with the spirit and intent of the regulations — and can be considered effective in achieving the intended results.
To aid in interpreting the CGMP regulations, the following comments are offered. They commence with an outline of some basic facts and then address the individual sections of the CGMP regulations.
Some Basic Facts
(1) All producers of medicated feeds are required to follow current good manufacturing regulations, whether they are in commercial practice, on-farm operations or non-commercial feed mills.
(2) Depending on the drug sources used to produce medicated feeds, all producers of medicated feeds are divided into two groups — (a) those who must register with FDA and obtain a medicated feed mill license and (b) those who are not required to register. This division determines which portion of the CGMP regulations must be observed.
(3) Drugs are divided into two categories — Category I and Category II. Category I drugs require no withdrawal before animals are marketed. Category II drugs have a withdrawal associated with their use or require special consideration.
(4) Drug sources are divided into two types — Type A medicated articles and Type B medicated feeds. Type A products are comparable to standardized drug premixes. Type B products are comparable to feed concentrates or supplements. As such, Type B feed covers a wide range of drug potencies. Type B products are intended for mixing purposes.
NOTE: The third type product — Type C medicated feeds — are complete or free-choice products not intended for mixing.
(5) Any medicated feed producer using one or more Category II, Type A drug sources must register with FDA, obtain a medicated feed mill license and is subject to the more detailed CGMP regulations, Sections 225.1 through 225.115. Registered facilities are subject to inspection by FDA or state agents on a biennial basis for compliance.
The requirement for registration and approved licenses applies to all classes of feed producers — commercial, local dealer/mixers, integrated operations and on-farm mixers. There are no exceptions if one uses one or more Category II, Type A drug sources. The dual requirement also applies to anyone producing a medicated free-choice feed — regardless of the drug or its source.
(6) Medicated feed producers using only Category I drugs, regardless of type source and/or Type B Category II drug sources, are not required to register with FDA or obtain a license. As non-registrants, they are subject to the less detailed CGMP regulations — Sections 225.120 through 225.202. Non-registered facilities are not subject to routine FDA inspection. They may be inspected for cause or by state officials.
(7) Federal law prohibits veterinarians from prescribing animal drugs for feeds. No one, including a veterinarian may exceed the limits of the approved animal drug in federal regulations, mix approved animal drugs in feeds for animals not listed in the federal regulation for the particular drug or for a different production class not listed in the regulation. Currently, all approved animal drugs permitted for use in feed are available over-the-counter and do not require a prescription. However, two approved drugs (with four separate uses) require a veterinary feed directive (VFD).
CGMPs for Licensed Mills
Section 225.1 — Current good manufacturing practice
Subsections (a) and (b) provide a capsule summary of background and purpose of the CGMP regulations.
Section 225.10 — Personnel
The shortest but most important section of the CGMP regulations. A team of qualified individuals with appropriate direction and supervision is the key element for any successful operation. Direction includes written instructions and supervision includes assurance of familiarity with those instructions. Focus is on training, experience and supervision.
Section 225.20 — Buildings
Appropriate facilities are required which are capable of their intended purpose of feed production coupled with good interior and exterior housekeeping. Housekeeping aids in preventing pest and insect infestation and in preventing contamination of all kinds. Appropriate facilities and good housekeeping are required.
Section 225.30 — Equipment
Similar to “Buildings,” equipment must be capable of intended purpose and well maintained. Focus is on capable equipment and good maintenance. One specific item under equipment is the stipulation to test scales and metering devices at least once per year.
Section 225.35 — Use of work areas, equipment and storage areas for other manufacturing and storage purpose
To preclude contamination of feed by such materials, fertilizer, herbicides and pesticides must be kept out of feed manufacturing areas and equipment. Focus is on prevention of contamination by physical separation.
Section 225.42 — Components
“Components” refers to drug sources. A comprehensive approach to administrative quality control over drug components is outlined. It begins with screening upon receipt and the establishment of a recordkeeping system that provides continuing drug identity and a complete history from receipt through use of the drug component to produce medicated feed. The heart of this control system is the maintenance of a drug inventory, a periodic timely comparison of that inventory with the actual physical inventory and immediate appropriate action should there be significant difference. Inherent in this system is the use of drug sources on a first-received, first-used basis. Records can be a series of interrelated records — i.e., they need not take the form of a single comprehensive record. They should permit the tracing of a given lot of drug from point of receipt through use of that drug.
Section 225.58 — Laboratory controls
This section complements the foregoing section on controls. Assays are spot checks on these primary controls. The assay requirement is specific. The first batch of feed produced under an approved license is to be sampled and analyzed. Thereafter, three random samples and analyses are to be conducted per year. If the medication is a combination of drugs, only one need be analyzed each time with a rotation of drugs analyzed.
Any out of tolerance assays must be followed up with an investigation as to cause and any needed corrective action taken. Document the investigation and action taken. If deemed necessary, distribution of feed analyzed should be discontinued. The inherent lag between sampling and analytical results and the normal quick use of feed often makes this action moot.
To what extent an out of tolerance assay result needs to be investigated is an unresolved issue often arising in the course of mill inspections. Certainly there is a need to immediately review all pertinent records, check on probable causes, make a determination and take appropriate action. The investigation should be thorough, the action taken in line with the circumstances — and a complete record made for future reference.
NOTE: The assay procedures for some drugs are not considered reliable and problems with good methods occasionally surface. If recurring problems are encountered, it is suggested a separate “problem” file be established and the help of the drug manufacturer be requested. Remember, assays by state feed control officials are accepted by FDA. However, the tolerances or assay limits established by FDA for each drug are not necessarily in agreement with the analytical variations adopted by AAFCO for each drug. Thus, if a drug assay is considered within tolerance by a state, it may be out-of-tolerance by the FDA (e.g., bacitracin AAFCO AV=40%, FDA assay limit = 30%). Check the tolerances established for each drug listed on the medicated feed application. In the CPGM FDA will accept a lot of medicated feed to be considered within assay limits if one or more drugs in a medicated feed manufactured from a fixed drug Type A combination is found within assay limits. This concession by FDA recognizes that fixed drug Type A premixes from a supplier are not allowed to leave the Type A plant unless all drugs are within assay limits.
Section 225.65 — Equipment cleanout procedures
The twin primary goals of the CGMP regulations are medicated feeds proper in all respects and the protection of the integrity of all other medicated and non-medicated feeds. Equipment cleanout addresses this second goal. The thrust is to minimize and control carryover of a drug into subsequent production — i.e., prevent unsafe carryover. That carryover exists as a recognized fact, as is the need to control it. A number of control procedures are outlined. The most common control utilized is to schedule production with an appropriate sequence that directs carryover to a safe haven. Sequencing should be on a predetermined basis. Practicality points to a system of priorities based on the inherent nature of drugs and feed types, with absolute prohibitions where needed. For example, common sense dictates a complete swine finishing feed should not follow a sulfa-containing feed, that the two feeds should be separated as much as possible by other production. The same is true of ionophore-containing feeds and horse feeds and of lincomycin and rabbit feeds.
Again, the goal is to prevent unsafe carryover by utilizing all reasonable, practical means. While the means should be defendable, the actual burden of proving unsafe carryover rests with FDA.
Unsafe carryover is not specifically defined. Unfortunately, information is sparse on the effect of trace amounts of an animal drug in a non-target animal feed. For the most part, common sense must be exercised in setting up a sequencing procedure and priorities as to first and subsequent preferences of order of feed production. For example, it makes sense to group the production of similarly medicated feeds when this is possible and to do so — again, when possible — in order of decreasing potency. It also makes sense to follow such production with feed for an animal for which the drug is approved — and preferably a concentrate or supplement form of feed which will be further diluted. This might be construed a first priority approach.
The practical realities of feed manufacturing dictate the necessity of having other alternatives available.
NOTE: Sequencing and drug carryover are well covered in two FDA compliance policy guides entitled, “Unsafe Contamination of Animal Feed from Drug Carryover” (CPG 680.500) and “Sequencing as a Means to Prevent Unsafe Drug Contamination in the Production, Storage and Distribution of Feeds” (CPG 680.600). Both of these short publications are available from any FDA district office, FDA headquarters or online at www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/default.htm.
Section 225.80 — Labeling
Correct labeling is essential. All appropriate steps must be taken to insure labels are correct when printed, are current when used and accompany the right feed at all times. Standard procedure should require immediate disposal of all outdated feed labels to prevent mislabeling accidents.
Section 225.102 — Master record file and production records
This is the longest section of the CGMP regulations but one having a single, simple objective — a complete and meaningful history of medicated feed production — that history running from formulation to the point of distribution.
Two points bear mention. First, the master record file is not necessarily a comprehensive single file. It can be and usually is a collection of files — formulation, manufacturing instructions and controls imposed. As such, these files may be rightfully located in different areas of the establishment. Second, all records should carry the identification of the person responsible for them. This is usually accomplished by signing or initialing. Only by knowing who to question can questions be answered. This accountability factor applies to all records.
In the case of computerized records or transmissions from a central office, initialing or signing may be a practical impossibility and some other form of accountability will need to be devised. Also, in order to use computerized or electronic records, facilities must comply with FDA’s Part 11, Electronic Recordkeeping and Electronic Signatures (Title 21, C.F.R. Part 11), which applies to the CGMP regulations. Most firms utilize paper records or printouts from computerized systems. Use of such paper records mean firms do not have to comply with the complicated Part 11 validation requirements.
Section 225.110 — Distribution records
The records required are the normal business records of product distribution. Coupled with label codes and operation on a first-made, first-shipped basis, they should enable product to be traced to the field and product in the field to be traced back through the system. This capability is needed to facilitate recall or investigate the cause of field problems.
Section 225.115 — Complaint files
This section requires a record be maintained of each medicated feed complaint and the action taken on the complaint. This applies to written and oral complaints about the feed attributable to its drug content only. Such complaint records are usually held in a separate file apart from non-drug oriented complaints.
Since feed manufacturers are not drug experts, it is appropriate to involve the drug manufacturer who can more accurately evaluate questions of safety and effectiveness. The complaint file is only required to contain those complaints related to the medicated feed. Although this may be difficult to determine, it certainly does not include complaints regarding off-odors, "fines" or other non-medicated issues. This type of file is only required for federally licensed mills and only related to approved new animal drugs requiring a medicated feed mill license.
CGMP Sections for Non-Licensed Facilities
NOTE: FDA, with industry input, published a straightforward booklet, “CGMPs for Medicated Feed Manufacturers Not Required to Register with FDA”. This booklet can be obtained from the following web site: www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052386.pdf. The following comments parallel the contents of that publication.
Section 225.120 — Buildings and grounds
Emphasis parallels that of Section 225.20 — i.e., suitable buildings and good interior and exterior housekeeping.
Section 225.130 — Equipment
Equipment must be capable of intended function and adequately maintained in a clean and orderly fashion.
Section225.135— Work and storage areas
Tracks Section 225.35 in specifying exclusion of fertilizers, herbicides and pesticides from feed areas and equipment to preclude contamination.
Section 225.142 — Components
Requires procedures to identify, protect and control the use of drug sources — both Type A and Type B sources. Reference is made to “inventory control” on the receipt and use of drug sources. While specifics are not given, a form of inventory control similar to that described in Section 225.42 should be considered in the interests of good business practice. There is a specific requirement that all drug sources be used in conformance with label directions. Focus is on identification, protection, control and conformance with directions for use.
Section 225.158 — Laboratory assays
No assays of medicated feeds are required. However, if assays are performed, including assays by state control officials, with results outside accepted limits, there must be an appropriate investigation and any necessary corrective action. Focus is on reaction to indication of a possible problem.
Section 225.165 — Equipment cleanout procedures
This is the shortest section, but a vital one, applicable to non-licensed mills. Complete focus is on preventing unsafe carryover. (See comments on Section 225.65.)
Section 225.180 — Labeling
Label controls must result in correct and complete labels and the correct matching of labels and feeds. Focus is on labeling correctly in all respects.
Section 225.202 — Records
Records must provide a history of formulation, production and distribution and be adequate for recall purposes. Focus is on a documented record and recall capacity.
Electronic Records and Signatures
FDA published this new section in the federal regulations (21, CFR Part 11) several years ago, and AFIA believed that it did not properly apply to the feed industry. However, FDA enforces this provision on firms for which a predicate rule is in effect. As the medicated feed CGMPs are a predicate rule, then firms must comply with the Part 11 provisions.
Basically, a firm must certify to FDA that its computer systems used in lieu of paper records are validated and work like the manufacturer of the computer systems say it should work. Nearly all firms decided this was a very cost intensive process and likely one to present regulatory concerns, so the legal way to comply with this regulation is to ensure all records are printed, signed, filed and made available for copying as required in the specific regulations. Any computerized record or electronic signature for which a paper record has not been created, makes compliance with these provisions mandatory.
The enactment of the Food Safety Modernization Act (FSMA) by Congress and signing into law by the President on Jan. 4, 2011, will have a significant impact on the feed industry. However, this law does not apply to medicated feed and FDA says the cGMPs will not change, including the one year record retention requirement, which is two years in FSMA. What will change is the impact of this new law on the other ingredients in medicated feed, and FDA will likely do both cGMP inspections and FSMA inspections at the same time.
Good manufacturing practices are synonymous with good business practices. CGMP regulation emphasis is on good housekeeping, predetermined systematic procedures, effective controls and records providing a meaningful history of the operation. CGMPs are founded in past experience, but must be ever subject to modification or fine tuning in light of recent experience and new information.
Good manufacturing practices, their determination and how to comply, are fluid subjects requiring a continuing exchange of information, viewpoints and ideas. Enforcement through mill inspections often reveals shades of difference between the feed industry and FDA. The ongoing resolution of these differences on what constitutes a good manufacturing practice is a must so there is common understanding.