Medical Gases

Sec. 435.100 Compressed Medical Gases - *Warning Letters for Specific Violations Covering Liquid and Gaseous Oxygen* (CPG 7132a.16)

BACKGROUND:

*This CPG provides guidance for issuing warning letters to firms processing compressed medical gases in violation of the adulteration, misbranding, and/or new drug provisions of the Federal Food, Drug, and Cosmetic Act.*

Compressed medical gases, *including compressed medical oxygen and liquid oxygen, *are drug products regulated under 21 CFR 210 and 211.

*Section 201.100 requires that the labeling for prescription drugs (e.g., Oxygen U.S.P.) bear adequate directions for use. In this regard, the requirements of 201.100 would be satisfied if the article meets the labeling requirements described in the Federal Register of March 16, 1972, (37 FR 5504) entitled "Oxygen and Its Delivery Systems, Proposed Statement of Policy." Although this proposal was not finalized and is being revoked, the Agency continues to use it as a labeling guideline for medicinal oxygen.

Oxygen, U.S.P. would be misbranded if its label fails to indicate whether or not it has been produced by the air-liquefaction process as required by the United States Pharmacopeia (USP XXII).

All other compressed medicinal gases should meet the requirements of 21 CFR 201.161.

All medical gas drug labels must bear the following information: (1) name and address of the manufacturer or distributor, (2) official product name (for single-component gases), (3) contents, in units of measure commonly used, e.g., liters, cubic feet, (4) lot number, and (5) statement of ingredients (for gas mixtures).*

Section 211.160(b) requires the establishment of scientifically sound and appropriate specifications and test procedures that are designed to assure that components and drug products conform to appropriate standards of identity and strength.

Section 211.160(b)(4) requires the calibration of laboratory instruments, apparatus, and gauges at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met.

Section 211.165(a) requires that each batch of a drug product be tested to determine satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release.

Section 211.165(e) requires that the accuracy, sensitivity, specificity, and reproducibility of the test methods employed by a firm shall be established and documented.

The Center for Drug Evaluation and Research *(CDER) "Compressed Medical Gases Guideline" (revised February, 1989) provides guidance to industry for compliance with these regulations. Many firms that fill high pressure cylinders with medical gases do not assay the finished product for identity and strength. In some instances, the testing performed is inadequate, due to failure to: 1) establish appropriate finished product test procedures and specifications, and/or 2) maintain the test apparatus, e.g., the United States Pharmacopeia Orsat test apparatus, or calibrate the oxygen analyzer according to the analyzer manufacturer's specifications.

Of particular concern is the transfilling (cascading) of smaller high pressure cylinders (e.g., E or D) from larger high pressure cylinders (e.g., H or K). The smaller high pressure cylinders may be transfilled individually, or more than one may be filled at a time by connecting them to a manifold with multiple outlets. The firms may fail to perform any finished product testing and to vacuum evacuate or double purge each cylinder prior to filling. Many of the firms have not been registered and are unaware of their responsibility to comply with the current good manufacturing practice regulations.

HOME RESPIRATORY CARE:

The revised guideline (February 1989) includes guidance for home respiratory care companies (HRC). In practice, an HRC may pick up or receive a shipment of liquid oxygen (LOX) in a cryogenic container and transport the container to a patient's home to fill a cryogenic home unit. Another common practice is for the HRC to exchange a full unit with the empty home unit. The empty units are returned to the HRC facility for filling. In both scenarios, no testing of the cryogenic home units is required, provided all of the following three elements are met:

1. The incoming LOX has been adequately tested for identity and strength by one of the methods outlined in the guideline,

2. no other liquid (gas) is being transfilled on the premises, and

3. the cryogenic home units are retained by the HRC.

However, if any other liquid (gas) is being transfilled, then ALL cryogenic home units would require full USP testing.

Furthermore, in accordance with Section 211.87, the contents of units sent out for repair/maintenance, must be retested at the least for identity, prior to redistribution.

Occasionally, an HRC will use a supplier's Certificate of Analysis (COA) to reduce the amount of testing the HRC needs to perform. In this situation, the following minimum information should be provided in the COA:

1. supplier's name

2. name of product (gas)

3. air-liquefaction statement

4. lot number or other unique identification number

5. actual analytical results obtained for identity and strength

6. test method used for analysis (Note: In lieu of indicating the test method on each COA issued, a general letter from the supplier, maintained on file with the HRC, which indicates the test method used for all supplied product is acceptable)

7. supplier's signature/date.

If the HRC relies on a COA to reduce the amount of testing it needs to perform, the HRC should establish the reliability of the supplier's analysis at appropriate intervals (once a year would be sufficient) by taking a recently delivered and tested vessel to a third party for full USP testing.

Most medical gas firms receive their bulk oxygen from an intrastate source. If they receive LOX from an interstate source, document the interstate movement of the bulk LOX. If the LOX is from an intrastate source, document the interstate movement of 1) the stand tank, 2) the large cryogenic vessels, 3) the high pressure cylinders, and/or 4) the home units, by determining the location of the manufacturer of the articles.*

REGULATORY ACTION GUIDANCE:

*District offices should consider issuing warning letters under any one of the following circumstances, provided interstate movement of the gas or the various containers (cryogenic or high pressure cylinders) has been documented:*

1. Firm has no written specifications or test procedures, or if such documents exist, they are not in the possession of, or are not followed by the individual(s) performing the assay.

Charge: 501(a)(2)(B); 21 CFR 211.160(b)

2. *Firm is using a Servomex Oxygen Analyzer <>, for example, or other testing instrument for oxygen analysis and fails to adequately calibrate the instrument according to the manufacturer's directions, i.e., daily or more often, using the calibration gases specified.

Charge: 501(a)(2)(B); 21 CFR 211.160(b)(4)

<> Since oxygen is the only gas that will provide a significant reading on the scale of a calibrated Servomex Oxygen Analyzer, the strength reading obtained also serves as an identity test.

3a Firm is using a manifold to fill high pressure cylinders with a single compressed medical gas such as Oxygen, USP, or Nitrogen, NF, from a bulk storage tank containing commingled lots of the gas and fails to assay the contents of the cylinders for both identity and strength prior to release. (Instead of testing each cylinder, it is acceptable to perform an assay for identity and strength on one filled cylinder per manifold filling sequence.)

3b Firm is filling small high pressure cylinders individually or one at a time from larger high pressure cylinders, but fails to assay at least one cylinder per uninterrupted filling sequence for both identity and strength, provided the same equipment, personnel, and lot of bulk is used.

3c HRC fails to test the incoming liquid oxygen for both identity and strength according to one of the methods outlined in the February, 1989, Compressed Medical Gases Guideline.

Charge: 501(a)(2)(B); 21 CFR 211.165(a)

4. Firm is using a non-official test procedure for the assay of Oxygen, USP, and has no documentation that the sensitivity and accuracy of the test procedure will produce identity and strength results equivalent or superior to those obtained using the official test procedure.

Charge: 501(a)(2)(B); 21 CFR 211.165(e)

5. The article is misbranded in that its labeling fails to contain a statement of the quantity of the contents.

Charge: 502(b)(2); 21 CFR 201.51

6. The article is misbranded in that it is regarded as a prescription drug and its labeling fails to bear adequate directions for use in accordance with 21 CFR 201.100(c).

Charge: 502(f)(1); 21 CFR 201.100(c)

7. The article, Oxygen USP, is misbranded in that its labeling fails to indicate whether or not the oxygen has been produced by the air-liquefaction process as required by the United States Pharmacopeia (USP XXII).

Charge: 502(g)

8. The article is misbranded in that it was manufactured in an establishment not duly registered under section 510 of the Act and the article has not been listed as required by section 510(j).

Charge: 502(o); 21 CFR 207.20

9. The article is a drug within the meaning of section 201(g) of the Act which may not be introduced or delivered for introduction into interstate commerce under section 505(a) of the Federal Food, Drug, and Cosmetic Act, since it is a new drug within the meaning of section 201(p) of the Act and no approval of an application filed pursuant to section 505(b) is effective for such drug.

Charge: 505(a)

Examples of the wording to be used in the warning letter to any filler of medical gas are as follows:

501(a)(2)(B) Your product, (name of medical gas), is adulterated in that the controls used for the manufacture, processing, packing, or holding of this product are not in conformance with current good manufacturing practice regulations (Title 21, Code of Federal Regulations, Parts 210 and 211), such as:

Failure to establish scientifically sound and appropriate test procedures for the assay of (name of medical gas(es)) 21 CFR 211.160(b)].

Failure to properly calibrate the Oxygen Analyzer used for the assay of Oxygen, USP, in that your firm did not have the high purity nitrogen standard required to calibrate the "zero" on the meter [21 CFR 211.160(b)(4)].

Failure to assay the filled high pressure cylinders of (name of medical gas) for identity and strength, prior to release [21 CFR 211.165(a)].

Failure to establish that the test procedure used to determine the strength and identity of (name of medical gas) will provide test results that are equivalent or superior to the official test procedure. (Give example of why it isn't equivalent or superior to the official test procedure) [21 CFR 211.165(e)].

In addition, the following is an example of the wording for HRCs that fill liquid home units:

Failure to assay the incoming liquid oxygen for identity and strength prior to filling the liquid home units [21 CFR 211.165(a)].

In addition, the following violations, if noted during the inspection may be included in the District's letter:

Failure to test each lot of bulk oxygen to determine conformance with appropriate specifications for identity and strength [21 CFR 211.84(d)(2)].

Failure to perform adequate prefill operations on each high pressure cylinder, prior to filling [21 CFR 211.84(d)(3)].

Failure to establish written procedures designed to assure that the drug products have the identity and strength they purport or are represented to possess [21 CFR 211.100(a)].

Failure to establish written procedures for the reconciliation of the quantities of labeling issued, used, and returned [21 CFR 211.125(c)].

Failure to establish written procedures designed to assure that correct labels and labeling are used, including identification of the drug product with a lot or control number that permits determination of the history of the manufacture and control of the batch [21 CFR 211.130(b)].

Failure to establish adequate batch production and control records for each batch of drug product produced, including documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished [21 CFR 211.188(b)].

Failure to maintain complete records of the periodic calibration of the oxygen analyzer, CFR 211.194(d)].

Failure to establish written procedures for the receiving of any complaints [21 CFR 211.198].

When issuing a warning letter to a firm with multiple locations, the original should be sent to the most responsible head residing at the headquarters location, with a copy sent to the plant manager. The warning letter should include a statement that this will serve as official notification to management that FDA expects all locations to be in compliance.

Once a firm as been issued a warning letter, the next course of action, provided the firm continues to operate out of compliance, is to consider submitting a seizure recommendation to CDER. Do not to issue a second warning letter.

Send a copy of the warning letter that issues to the firm to Duane S. Sylvia, HFD-322, Sterile Drugs Branch, Division of Manufacturing and Product Quality, CDER.

*Material between asterisks is new or revised*

<> Indicates material has been deleted

Issued: 11/5/87
Revised: 8/31/92

Sub Chapter 440

New Drugs

Sec. 440.100 Marketed New Drugs Without Approved NDAs or ANDAs (CPG 7132c.02)

BACKGROUND:

Prior policy under the DESI program had permitted a firm to market a new product upon the submission of a New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) as long as the new product was identical to a prescription drug product that had been evaluated as "effective". The history and justification for this approach were described in a FEDERAL REGISTER notice published on June 20, 1975 (40 FR 26142, see paragraph I(D)(5) on pp. 26144-45). This policy was challenged and overturned in a lawsuit on July 29, 1975 (Hoffman-La Roche v. Weinberger, 425 F.Supp. 890 (D.D.C. 1975)). The Court held that if FDA had declared a prescription drug product to be a "new drug", the agency could not permit any identical, similar, or related product to be marketed without prior approval of an NDA or ANDA. The complete text of this decision was published in a FEDERAL REGISTER notice on September 22, 1975 (40 FR 43531). Subsequently, the Court granted certain exceptions to this ruling, but these exceptions are not applicable to DESI effective drugs. The amendment to the Court's order was published in the FEDERAL REGISTER on March 2, 1976 (41 FR 9001). It should be noted that all drugs in the DESI review are "new drugs" under the law.

As a result of this decision, the agency has reevaluated its policy, the resources available to process NDAs and ANDAs and to handle violations of the law, and the alternative policies which might be used to protect the public health and safety within the requirements of the Federal Food, Drug, and Cosmetic Act. The agency has decided to reaffirm that all products marketed as drugs under the DESI program are new drugs, and therefore, require an approved NDA or ANDA for marketing. In view of the reaffirmation of this policy, the agency must proceed to remove from the market all current DESI-effective prescription products that are not the subjects of approved NDA's or ANDA's, and to prevent in the future the marketing of such unapproved products.

The agency is aware that many firms are marketing products without approved new drug applications that are related to DESI effective prescription drugs. In order to achieve uniform compliance with the Court Order, all violative products must be identified and removed from the market. With the resources presently available for attaining industry-wide compliance, this goal will take several years to achieve. Considering the magnitude of the problem, the limitation on FDA's resources, and the resulting long time period before compliance can be fully attained, the agency has developed a strategy to handle unapproved products on a priority basis. The priorities for enforcement action relate to a particular drug's effect on public health and safety, and are designed to have a maximum impact on violative products and to provide equitable treatment among competing firms. This strategy also integrates with ongoing compliance programs directed at DESI-effective prescription drugs, OTC Category II products, and post-1962 NDA prescription drugs, and anticipated compliance programs directed at DESI-Paragraph XIV prescription drugs (those requiring additional studies before a decision on effectiveness can be made), and pre-1962 new drugs which were not part of DESI.

POLICY:

Part A of this section outlines the sequence for relating drugs for which final determinations have been made regarding their new drug status and for which FEDERAL REGISTER notices have been published requiring ANDA or NDA approval for marketing them. All products within each category will be treated in the same fashion regardless of the size of the firm.

The Center for *Drug Evaluation and Research* will implement Part A of this policy by identifying those marketed drug products which are within the Part A categories named below. The District Offices will then initiate regulatory action against any violative products on the market in accordance with a Compliance Program regarding that specific category of drugs. This procedure will be repeated for each category until overall compliance is achieved. The *CDER* may from time to time add drugs to any category.

Part B of this section covers the regulation of those drugs for which final determinations regarding their regulatory or legal status have not been made.

1. DESI PRESCRIPTION DRUGS WHERE FINAL DETERMINATIONS ON EFFECTIVENESS HAVE BEEN MADE.

Category I - Ineffective Drugs

These are covered by an ongoing program (C. P. 7352.001) and will remain top priority.

Category II - Bio-Problem Drugs

This category consists of DESI-effective prescription drugs with known or potential bioavailability or bioequivalence problems.

Approximately 171 drug entities have been identified in this group. Regulatory action has already been initiated on those identical drugs identified in the DHHS Publication No. (FDA) 76-3009 (revised 6/76). The General Program (C.P. 7352.002) covering this category has issued and follow-up to this category is ongoing under Compliance Program Circular PC 7352.002D.

Category III - Top 200 Prescription Drugs

This category consists of the "Top 200" most widely prescribed drugs that have been DESI-rated as effective. This category does not include antibiotics, topical preparations, and those drugs listed in Categories I and II.

An initial survey indicated that there were approximately 25 drug entities in this category requiring attention. These "Top 200 Prescription Drugs" are identified in Program Circular 7352.002E. Regulatory Letters have issued from District offices to all known manufacturers of unapproved drugs subject to this category.

Category IV - Bio-Related Drugs

This category consists of all the prescription drugs related to those in Category II (i.e., drugs containing one or more of the listed ingredients). This category includes combinations, related chemical forms and related dosage forms, including controlled release. It excludes topical preparations. Controlled release preparations may warrant separate attention but this requires further evaluation. These "bio-related drugs" have been handled under Program Circular 7352.002C and regulatory letters have issued to all known manufacturers of unapproved drugs subject to this category.

Category V - Other Identical DESI-Effective Prescription Drugs

This category consists of those products that are identical to DESI-effective prescription drugs, excluding topical preparations, and are not covered by the preceding categories. These products will be handled under a Compliance Program similar to that used for Category II.

Category VI - Other Related DESI-Effective Prescription Drugs

This category consists of combinations and related chemical dosage forms including controlled release. It excludes topical preparations. Products subject to this category will be handled under a Compliance Program similar to that used for Category II.

Category VII - DESI Effective Prescription Topical Preparations Identical and Related

This category consists of all the topical preparations for the drugs covered in Categories I-VI. These products will be handled under a Compliance Program similar to that used for Category II.

B. DESI AND OTHER PRE-1962 PRESCRIPTION DRUGS WHERE FINAL DETERMINATIONS ON THEIR REGULATORY OR LEGAL STATUS HAVE NOT BEEN MADE.

These drugs are covered by the categories outlined below and may be worked into the regulatory scheme described under Part A above as final determinations are made regarding their effectiveness, new drug status, or grandfather status.

DESI "Paragraph XIV" Prescription Drugs.

This category consists of prescription drugs that are currently exempted from regulatory action under Judge Bryant's Order. As final determinations are made regarding the effectiveness of these drugs, they will be handled under the appropriate Part A category on a continuing basis. That is, if a drug is downgraded to "ineffective" it will be handled under Category I, and if it is upgraded to "effective" it will be handled under one of the remaining Part A categories.

DESI "Less-Than-Effective" Prescription Drugs.

This category consists of prescription drugs for which final DESI determinations on effectiveness have not been made (e.g., possibly or probably effective drugs and those with current NOHs), other than those in the Paragraph XIV Category. As final determinations are made regarding the effectiveness of these drugs, they will be handled under the appropriate Part A category on a continuing basis.

Pre-1962 Prescription Drugs Covered by an NDA But Not Yet Reviewed by DESI.

A certain number of drugs covered by pre-1962 NDA's have not undergone a DESI review. Procedures are being implemented so that these drugs will be evaluated to determine their effectiveness. As final determinations are made on these drugs, they will be handled under the appropriate Part A category on a continuing basis.

Pre-1962 Prescription Drugs Not Covered by an NDA.

A certain number of drug products containing one or more active ingredients first introduced into the marketplace before 1962 are not covered by an NDA. These products are marketed based on their manufacturers' belief that such products are not subject to the new drug provisions of the act. Procedures will be implemented so that these products will be evaluated to determine whether the new drug provisions are applicable to them. If a final determination is made that a particular drug in this category requires an approved NDA or ANDA before marketing, the drug will be handled under the appropriate Part A category on a continuing basis.

POLICY GUIDELINE EXCEPTIONS:

While this policy guide represents a systematic approach to the implementation of the Court Order and the requirements of the new drug provisions of the act, it is not meant to preclude taking action against drugs outside of the established priorities under the following circumstances:

1. Including a new drug (505) charge (where appropriate) for a drug subject to this policy which become violative under another provision of the act.

2. Initiating regulatory action (as a new drug) against any drug subject to this policy should the agency receive significant new information which questions the safety or effectiveness of the drug.

3. Initiating regulatory action against any drug on the market without an approved new drug application if it is identical or related to a post-1962 NDA approved for safety and effectiveness or it contains a new chemical entity not previously marketed.

4. Initiating regulatory action against an unapproved prescription drug product first marketed after November 13, 1984, if the product differs from a product covered by Part B above in:

A. formulation (as described below);

B. dosage or strength;

C. dosage form;

D. route of administration;

E. indications for use; or

F. intended patient population.

A formulation will be considered different, if:

(1) the product contains a different active ingredient;

(2) the product contains a different quantity of an active ingredient;

(3) the product is a non-oral dosage form other than a topical preparation and it contains one or more different inactive ingredients, different amounts of inactive ingredients, or different proportions of inactive ingredients to the extent that the names, amounts, or proportions of inactive ingredients are required by regulation to be disclosed in labeling (see 21 CFR 201.100(b)(5)); or

(4) the product is an oral dosage form or a topical preparation and it contains one or more inactive ingredients not customarily used in such product.

Differences that result from compliance with a compendial standard or an FDA requirement will not cause a product to be subject to this exception.

5. Initiating regulatory action against an unapproved prescription drug product covered by Part B above, if after November 13, 1984, a change is made in:

A. the product's formulation (as described below);

B. the product's dosage or strength;

C. the product's dosage form;

D. the product's route of administration;

E. the product's indications for use; or

F. the product's intended patient population.

A formulation will be considered different, if:

(1) the product contains a different active ingredient;

(2) the product contains a different quantity of an active ingredient;

(3) the product is a non-oral dosage form other than a topical preparation and it contains one or more different inactive ingredients, different amounts of inactive ingredients, or different proportions of inactive ingredients to the extent that the name, amounts, or proportions of inactive ingredients are required by regulation to be disclosed in labeling (see 21 CFR 201.100(b)(5)); or

(4) the product is an oral dosage form or a topical preparation and it contains one or more inactive ingredients not customarily used in such a product.

Changes that are made to comply with a compendial standard or an FDA requirement will not cause a product to be subject to this exception.

*6 Initiating regulatory action against an unapproved drug product if a manufacturer, packer, or distributor fails to keep records or make reports regarding adverse drug reactions as required by Section 301.305.*

Aside from the exceptions mentioned above, the agency will adhere to the priorities as established. In addition, the *CDER* will deny FDA approval for contract purchase by other Federal government agencies (DOD, VA, PHS) of any drug subject to this policy which does not have an approved NDA or ANDA.

*Material between asterisks is new or revised*

Based on final rule published in Federal Register of 9/2/86 (51 FR 1476)

Issued: 10/6/76 as 7132c.08
Revised: 4/1/81, 9/19/84, 5/8/87, 3/95

Sec. 442.100 New Drugs - Export (CPG 7132c.01)

BACKGROUND:

The question has been raised as to whether or not a drug for which an NDA has been submitted, could legally be exported for commercial distribution before the NDA was approved.

POLICY:

Section 801(d) of the Act provides an exemption from the adulteration and misbranding provisions only and does not authorize exportation of a new drug that is not covered by an approved NDA.

However, under the provisions of 21 CFR 312.1, a new drug, limited to investigational use may be exported only for purposes of clinical investigation and not where the drug is intended for commercial marketing, or use in routine medical practice.

NOTE: See CPG 7150.11 (See Sec. 110.200 for this CPG.) covering export of FDA controlled products (including NDA/IND drugs) from Foreign Trade Zones.

Issued: 10/1/80

Sec. 444.100 Recovery of Investigational New Drugs From Clinical Investigators (CPG 7132c.05)

INTRODUCTION:

This compliance guidance document is an update to the Compliance Policy Guides Manual (August 1996 edition), revising an existing CPG. It will be included in the next printing of the Compliance Policy Guides Manual. It is intended for FDA personnel and is available electronically to the public.

This guidance document represents the agency's current thinking on the recovery of investigational drugs from clinical investigators. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.

BACKGROUND:

There are a number of instances when it is necessary to retrieve investigational new drug products that have been distributed under Investigational New Drug (IND) applications. There also has been inconsistent terminology used to classify the recovery of these products. FDA is, therefore, updating this policy guide to clarify the terminology used to classify the recovery of investigational new drugs from clinical investigators consistent with existing regulations. (See 21 CFR Parts 312.38(b), 312.45(b), and 312.59).

DEFINITIONS:

Recall, as defined in the Regulatory Procedures Manual (RPM), means a firm's removal or correction of a marketed product that FDA considers to be in violation of the laws it administers and is no longer under the direct control of the manufacturer or primary distributor.

Stock recovery, as defined in the RPM, is more appropriately applied to the return of investigational new drugs because the sponsor of the IND continues to exert direct control over the drug during the investigational stage of drug development.

POLICY:

The retrieval of investigational new drugs from clinical investigators by the sponsor of the IND or his/her agent is considered stock recovery. Recovery of these products is not considered a recall as defined in the RPM, whether precipitated by product defect, disqualification of the individual investigator, discontinuation or completion of a particular clinical study, or termination of the entire IND. Because FDA regulations protect the confidentiality of information related to new drugs being studied under INDs, the retrieval of these products are not included in the FDA weekly Enforcement Report.

The use of "recall" in 21 CFR 312.44(a) refers to the retrieval of investigational drugs for which the IND has been terminated and for which the primary distributor (sponsor) retains full accountability and direct control. Thus, the retrieval of these products should be considered a stock recovery, not a recall as defined in 21 CFR 7.1(g) (and the RPM), because such products are investigational, not marketed products.

For the above reasons, all investigational new drug product retrievals under the control of clinical investigators should be classified as stock recoveries since the sponsor continues to exert direct control over the stocks and distribution to the subjects in the study.

This policy also applies to new animal drugs being studied under INADs.

Issued: 10/1/80 Updated: 5/27/97

Sec. 446.100 Regulatory Action Regarding Approved New Drugs and Antibiotic Drug Products Subjected to Additional Processing or other Manipulations (CPG 7132c.06)

BACKGROUND:

FDA is issuing this policy guide to describe the circumstances in which the agency may initiate regulatory action regarding the marketing of approved new drugs and antibiotics that have been subjected to further processing or other manipulation, such as repacking, that is not covered by an approval under sections 505 or 507. (See U.S. v. Baxter Healthcare Corp., et al., CCH 38,166 Docket Nos. 89-2087/8 (7th Cir. May, 1990)).

Section 505 of the Federal Food, Drug, and Cosmetic Act (the Act) requires FDA approval of any new drug prior to marketing. Under the terms of that section, approval must be based on, among other things, the processes, facilities and controls used in the manufacture of the product. This is because various aspects of the manufacturing process, such as sterilization, mixing, filling, and packaging, can have a significant effect on safety and efficacy of a drug product.

Under section 507 of the Act, FDA requires an approved application, similar to an NDA under section 505, for any antibiotic to be exempted from the statutory requirement of batch certification. Thus, the agency conducts the same review, including an inspection of the manufacturer's facility, for approval of an antibiotic under section 507 as for approval of a new drug under section 505.

Under these provisions, each step in the manufacture and processing of a new drug or antibiotic, from handling of raw ingredients to final packaging, must be approved by FDA, whether carried out by the original manufacturer or by some subsequent handler or repacker of the product. Pharmacists are not exempt from these statutory requirements; however, the agency regards mixing, packaging, and other manipulations of approved drug by licensed pharmacists, consistent with the approved labeling of the product, as an approved use of the product if conducted within the practice of pharmacy, i.e., filling prescriptions for identified patients. Processing and repacking (including repackaging) of approved drugs by pharmacists for resale to hospitals, other pharmacies, etc., are beyond the practice of pharmacy and are thus subject to the requirements of premarket approval.

The only repacking outside the practice of pharmacy that has been sanctioned in the absence of FDA approval is that of solid oral dosage forms of products already approved under section 505. See U.S. v. Kaybel, Inc., et al., 430 F.2d 1346 (3d Cir. 1970) (repacking of approved Enovid (estrogen) tablets from large bottles into small bottles allowed without an additional approval under section 505).

The repacking of approved new drugs and antibiotics by entities outside the terms of the respective approvals has become much more common due to the increased demand for varied product package sizes, including products for "unit-dose" dispensing by doctors, pharmacists, and institutions. Agency policy concerning unit-dose labeling for oral and liquid oral dosage forms is stated in CPG 7132b.10 (See Sec. 430.100). The expiration dating and stability requirements for unit-dose repacked drugs are covered in CPG 7132b.11 (See Sec. 480.200). Custom repackers have responded to this increased demand by performing manipulations that are well beyond the intended uses approved in the labeling for pharmacists and physicians. Such manipulations result in new products whose safety and effectiveness have not been established. During the drug approval process, specifications are set for active ingredients, identity and limits for degradation products, sterility assurance, and closure integrity. Repacking by a new manufacturer may result in an unanticipated interaction between the pharmaceutical entity and the new packaging, such as absorption and degradation, which may affect the quality and purity of the product.

STERILE DRUG PRODUCTS:

The FDA has an even greater concern about the manipulation of approved sterile drug products, especially when the sterile container is opened or otherwise entered to conduct manipulations such as dissolving, diluting or aliquoting, refilling, resterilizing, or repackaging in new containers. The moment a sterile container is opened and manipulated, a quality standard (sterility) is destroyed and previous studies supporting the standard(s) are compromised and are no longer valid. These quality standards that include product stability and sterility must be restored.

Non-invasive manipulations may also raise questions of sterility, as when intact containers are repacked into a tray with other drugs, needles, gauze, etc., and the resulting package is sterilized and marketed as a unit for clinical use. Sterilization is an operation that must be documented and rigorously reviewed, and the FDA has consistently maintained that sterility is an absolute concept that must be ensured not only by sterility testing of the finished product, but also by validation of the sterilization process. Requirements for sterilization are covered in CPG 7132a.06 (See Sec. 410.100).

POLICY:

To protect the public health and to carry out its responsibility under sections 505 and 507, FDA will seek to ensure that all significant phases of the manufacture and processing of new drugs and antibiotics are approved. The agency may initiate regulatory action regarding the marketing of any new drug or antibiotic that has been subjected, for example, to any of the following manipulations, unless the manipulation is covered by an approval under sections 505 or 507: (1) mixing, (2) granulating, (3) milling, (4) molding, (5) lyophilizing, (6) tableting, (7) encapsulating, (8) coating, (9) sterilization, (10) repacking (including repackaging). The details of each manipulation, including the site(s) at which they will occur, must be the subject of an approved application or supplement filed pursuant to sections 505 or 507.

EXCEPTIONS:

Consistent with its enforcement policy subsequent to the Kaybel decision, the agency does not intend to initiate regulatory action with regard to the repacking of already-approved, solid oral dosage form drug products if (1) the repacking operation does not include any of the steps identified above, (2) the drug to be repacked is approved under sections 505 and 507, and (3) the labeling used for the repacked product is identical to that of the approved drug except for labeling changes necessary for compliance with section 502(b) of the Act.

In addition, the agency continues to regard manipulations that are performed within the practice of pharmacy, consistent with the approved labeling of the product, as approved uses of the product.

REGULATORY ACTION GUIDANCE:

Recommendation for regulatory action should be discussed with the Office of Compliance (HFD-310) prior to referral of the case.

Issued: 1/18/91

Sec. 448.100 Reconditioning of New Drugs which do not have Approved NDAs/ANDAs CPG (7132c.03)

BACKGROUND:

Prior policy under the DESI program permitted the marketing of new drugs evaluated as effective upon the submission of a New Drug Application (NDA) or Abbreviated New Drug Application (ANDA). This policy was challenged and overturned in a decision handed down on July 29, 1975, by the U.S. District Court for the District of Columbia (Hoffman La Roche vs. Caspar Weinberger, et al). The Agency implemented this order (Judge Green's decision) through Compliance Program 7332.26 covering products identical or related ("me too" drugs) to DESI drugs identified in a list published 1/76 (DHEW publication No. (FDA) 76-3009).

Agency policy as set forth in the program required that such new drugs be discontinued from marketing and recalled if substantial stocks remain in trade channels. When responsible firms have failed to initiate the above actions after being warned by issuance of a *warning letter*, unapproved new drugs have been seized.

Although recall or seizure may have been necessary for uniform enforcement and protection of the public health, destruction of such recalled or seized material is not always required provided adequate safeguards are taken.

POLICY:

In those instances in which an Abbreviated New Drug Application has been submitted and is currently pending, we will not insist upon destruction of recalled or seized material resulting from implementation of Compliance Policy Guide 7132c.02 involving DESI effective drugs provided:

1. Recalled stocks are quarantined by the formulator and not held by consignees, i.e., substantial stocks in the hands of consignees must be disposed of either by return to the formulator or by destruction. Failure to do so will result in recommendation for regulatory action by the district, preferably seizure.

2. Recalled (quarantined lots at the formulator) or seized material may not be released until and unless all the following conditions are met:

A. Approval of an NDA or ANDA is received.

B. The firm can validate that the lots in question were manufactured in accordance with the specifications of the approved NDA/ANDA including the following:

1. Compliance with CGMP.

2. Affected lots meet all purity, potency and labeling standards specified by the approved NDA/ANDA.

3. Where an unapproved new drug has been seized, under either Section 505 or 502, and as a result of subsequent ANDA approval it is not in the public interest that it be condemned and destroyed under Section 304(d)(1), the Agency may consider entering into a stipulation of dismissal incorporating the following principles:

(a) The claimant shall assure the Agency, by way of appropriate records, that the drug is in full compliance with the approved ANDA prior to dismissal of the complaint.

(b) Where consistency with the approved ANDA requires labeling modifications, and compliance cannot be assured by a records review as in *"a."* above, the Court may order the seized article be remanded to the custody of the claimant for the sole purpose of making the required modifications. If and when the Agency is satisfied that the required modifications have been made, and the article is in all respects consistent with the approved ANDA, the complaint may be dismissed.

(c) All activity undertaken to assure that the seized article is in compliance with the law shall be at the expense of the claimant, including investigatory and laboratory work performed by Agency personnel. Current fee and mileage schedules shall apply, and payment shall be received prior to dismissal of the action and full release of the article.

Where no NDA/ANDA has been submitted, or if the district has information that quarantined or seized lots will not meet the above conditions or approval of a current pending application does not appear probable within a reasonable time frame (three months), then we will insist upon destruction of stocks. In the case of the latter, concurrence by Division of Drug Labeling Compliance (HFD-310) is required.

Except upon the specific conditions outlined above, nothing in these provisions shall be construed as altering Agency policy that articles seized pursuant to Section 304 may not be reconditioned by Agency consent without the entry of a decree condemning the articles and providing for reconditioning under Agency supervision.

*Material between asterisks is new or revised*

Issued: 10/1/80
Revised: 3/95

Sub Chapter 450 - 457

OTC

Sec. 450.100 CGMP Enforcement Policy - OTC vs Rx Drugs (CPG 7132.10)

BACKGROUND:

Because of increased visibility and promotion of certain OTC preparations, there are periodic inquiries from district offices regarding whether or not the enforcement policy for CGMP regulations is the same for OTC drug products as it is for prescription (Rx) drug products.

Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act requires drugs to be manufactured in conformance with current good manufacturing practice. This section does not differentiate between OTC and Rx products and it was not intended by Congress to do so.

A prescription drug may be toxic or have other potential for harm, which requires that it be administered only under the supervision of a licensed practitioner (section 503(b)(1) of the Act). For this reason, problems associated with its manufacture are generally more likely to cause serious problems.

POLICY:

The CGMP regulations apply to all drug products, whether OTC or prescription.

REGULATORY GUIDANCE:

The selection of an enforcement action to be applied will be based on the seriousness of the deviation, including such factors as potential hazard to the consumer.

Issued: 4/1/82

Sec. 450.200 Drugs - General Provisions and Administrative Procedures for Recognition as Safe and Effective (CPG 7132b.15)

BACKGROUND AND POLICY:

An OTC drug listed in subchapter 21 CFR 330 is generally recognized as safe and effective and is not misbranded if it meets each of the conditions of 21 CFR 330.1 and each of the conditions contained in specific final monographs. Following the establishment of a final monograph, any related OTC drug that fails to meet the requirements of the monograph and 21 CFR 330.1 will be recognized as misbranded (Section 502 FD&C Act) or as a new drug requiring an approved NDA before it can be marketed (Section 505 FD&C Act). Prior to the final publication of a proposed monograph, it would not be in the agency's interest to pursue regulatory action unless failure to do so poses a potential health hazard to the consumer.

REGULATORY ACTION GUIDANCE:

*The "OTC Drug Monograph Implementation - General Program" (7361.003) includes a discussion of the intent of the monograph program as well as descriptions of the various advisory drug review panels and status of final monographs. This CP indicates that the primary responsibility for determining the compliance of OTC drug products lies with the *Center for Drug Evaluation and Research, Division of Drug Labeling Compliance, OTC Compliance Branch, HFD-312*.

Samples of OTC drugs, subject to a final monograph should not be submitted for regulatory action consideration under sections 502 or 505 of the FD&C Act without specific instructions from *CDER* to do so.

Samples of OTC drugs, not subject to a final monograph should not be submitted for regulatory action consideration on the basis of suspected labeling deficiencies unless there is a reasonable basis to conclude that the deficiency constitutes a potential hazard to health. Examples: 1) documented consumer injuries; 2) drugs requiring the prescription legend marketed as OTC; and 3) unwarranted claims for the treatment of serious disease conditions which could preclude obtaining proper medical attention.

This *guide* does not preclude the submission of regulatory action recommendations based upon adulteration charges.

*Material between asterisks is new or revised*

Issued: 10/1/80
Revised: 5/22/87, 3/95

Sec. 450.300 OTC Drugs - General Provisions and Administrative Procedures for Marketing Combination Products (CPG 7132b.16)

BACKGROUND:

The enforcement policy expressed in this document concerns the marketing of OTC drug products containing combinations of ingredients.

POLICY:

An OTC drug listed in subchapter 21 CFR 330 is generally recognized as safe and effective and is not misbranded if it meets each of the conditions of 21 CFR 330.1 and each of the conditions contained in the specific final monograph(s). Following the establishment of a final monograph, any OTC drug that is subject to the conditions of a final monograph and fails to meet the requirements of that monograph and 21 CFR 330.1 will be regarded as misbranded (section 502 FD&C Act) and/or a new drug requiring an approved NDA before it can be marketed (section 505 FD&C Act). In general, prior to final publication of a proposed monograph it is not appropriate to pursue regulatory action unless directed by headquarters.

REGULATORY ACTION GUIDANCE:

1. Products Under the OTC Review - OTC drugs subject to a final monograph should be submitted for regulatory action consideration under sections 502 and 505 of the FD&C Act, only as the appropriate compliance program or program circular instructs.

OTC drug combinations that were commercially marketed in the United States on or before May 11, 1972, and that are not subject to a final monograph should not be sampled for regulatory action consideration on the basis of suspected labeling deficiencies unless there is a reasonable basis to conclude that the deficiency constitutes a potential hazard to health. Examples include: (1) documented consumer injuries; (2) drugs requiring the prescription legend marketed as OTC; and (3) unwarranted claims for the treatment of serious disease conditions which could preclude obtaining proper medical attention (see CPG 7132b.15).

2. OTC combination drug products not marketed on or before May 11, 1972, are subject to the following policy:

A. Interim Marketing Permitted (at risk) - Marketing of a combination product not marketed on or before May 11, 1972, may begin if all of the following conditions are met:

(1) Each of the active ingredients in the combination has been commercially marketed in the United States on or before May 11, 1972, and is subject to the OTC Drug Review;

(2) Each of the active ingredients in the combination product has been classified by an OTC advisory review panel in Category I (generally recognized as safe and effective and not misbranded) in a published advance notice of proposed rulemaking;

(3) The combination of ingredients has been classified by an OTC advisory review panel in Category I in a published advance notice of proposed rulemaking; and

(4) The agency has not dissented from these panel recommendations.

Marketing of such a combination product must be in complete accord with all specifications in the advance notice of proposed rulemaking. In addition, such marketing is subject to the risk that the agency may subsequently adopt a different position that may require relabeling, recall, or other regulatory action. The Commissioner may state such position at any time by notice in the Federal Register, either separately or as part of another document; appropriate regulatory action may commence immediately and is not dependent on the publication of a final monograph.

B. Interim Marketing Not Permitted (pending subsequent notice) - A combination product not marketed on or before May 11, 1972, is considered a new drug and/or misbranded and is subject to regulatory action if any one of the following applies:

(1) A panel has recommended in a published advance notice of proposed rulemaking that the combination of ingredients or categories of ingredients be classified in Category I, and the agency has dissented from this recommendation;

(2) A panel has recommended that the combination be classified as Category II (not generally recognized as safe and effective or misbranded) or Category III (available data insufficient to classify as either Category I or Category II);

(3) A panel has recommended that one of the active ingredients in the combination be classified as Category II or Category III; or

(4) No OTC advisory review panel has considered the combination.

Any such combination product may be marketed only after (1) the Center for *Drug Evaluation and Research* or the Commissioner tentatively determines that the ingredients and the combination are generally recognized as safe and effective and the Commissioner states by notice in the Federal Register (separately or as part of another document) that marketing of the combination under specified conditions will be permitted; (2) the Commissioner determines that the combination is generally recognized as safe and effective and the combination is included in a published OTC drug final monograph; or (3) a new drug application for the product has been approved.

If no panel has considered the combination, the agency may propose to include the combination in a final monograph, but will allow a period for public comment. Ordinarily, such a proposal would not be made as a separate notice, but would be included at the next appropriate stage in the OTC Review rulemaking. Before marketing may begin, the comment period must have ended and a Federal Register notice must have been published setting forth the agency's determination concerning interim marketing.

*Material between asterisks is new or revised*

Issued: 5/1/84
Revised: 3/95

Sec. 450.400 Labeling and Distribution of OTC Drugs in Vending Machines (CPG 7132b.06)

POLICY:

There is no provision under the Federal Food, Drug, and Cosmetic Act which prohibits the sale of over-the-counter drug <> preparations in vending machines or in places other than drug stores. However, the article so vended must be in a full compliance with all the applicable sections of the Act.

The Act requires that certain mandatory labeling information must appear prominently, with such conspicuousness (as compared with other words, statements, designs or devices in the labeling) and in such terms as to render it likely to be read and understood by the ordinary individual under customary conditions of purchase and use. This means that the prospective purchaser must have an opportunity to read and take such information into consideration in reaching a decision whether or not to make the purchase. The vending machine should therefore bear a complete copy of the required labeling for the article being offered for sale or the article should be displayed in such a manner that the mandatory labeling can be viewed by the prospective purchaser.

<> Indicates material has been deleted

Issued: 10/1/80
Revised: 5/22/87

Sec. 450.500 Tamper-Resistant Packaging Requirements for Certain Over-the-Counter (OTC) Human Drug Products (CPG 7132a.17)

BACKGROUND:

*Requirements of the tamper-resistant packaging (TRP) regulations covering most OTC products were published by FDA in the FEDERAL REGISTER of November 5, 1982.

The regulations require that all OTC human drug products (except dermatologics, dentifrices, insulin and throat lozenges) (21 CFR 211.132), cosmetic liquid oral hygiene products and vaginal products (21 CFR 700.25), and contact lens solutions and tablets used to make these solutions (21 CFR 800.12) be packaged in tamper-resistant packaging.

The packaging must use an indicator or barrier to entry that is distinctive by design (such as an aerosol container), or must employ an identifying characteristic (a pattern, name, registered trademark, logo, or picture). Further, the regulations require a labeling statement on the container (except ammonia inhalant in crushable glass ampules, aerosol products, or containers of compressed medical oxygen) to alert the consumer to the specific tamper-resistant feature(s) used. The labeling statement is also required to be placed so that it will be unaffected if a TRP feature is breached or missing.

An amendment to the TRP regulations for OTC human drug products published as a final rule in the FEDERAL REGISTER on February 2, 1989. The new requirements (21 CFR 211.132(b)(1) and (2)) are:

1. For two-piece, hard gelatin capsule products subject to this requirement, a minimum of two tamper-resistant packaging features is required, unless the capsules are sealed by a tamper-resistant technology.

2. For all other products subject to this requirement, including two-piece, hard gelatin capsules that are sealed by a tamper-resistant technology, a minimum of one tamper-resistant feature is required.

Manufacturers were given until February 2, 1990, to comply with the new requirements.

In addition, the Agency has re-evaluated currently available tamper-resistant packaging technologies and concluded that some technologies as designed or applied are no longer capable of meeting the requirements of the TRP regulations.

POLICY:

A. PACKAGING SYSTEMS

Manufacturers and packagers are free to use any packaging system as long as the tamper-resistant standard in the regulations is met. The TRP requirements are intended to assure that the product's packaging "can reasonably be expected to provide visible evidence to consumers that tampering has occurred."

Examples of packaging technologies capable of meeting the TRP requirements are listed below. The use of one of these packaging technologies does not, by itself, constitute compliance with the requirements for a tamper-resistant package. Packaging features must be properly designed and appropriately applied to be effective TRP.

1. FILM WRAPPERS. A transparent film is wrapped securely around the entire product container. The film must be cut or torn to open the container and remove the product. A tight "fit" of the film around the container must be achieved, e.g., by a shrink-type process. A film wrapper sealed with overlapping end flaps must not be capable of being opened and resealed without leaving visible evidence of entry.

The use of cellophane with overlapping end flaps is not effective as a tamper-resistant feature because of the possibility that the end flaps can be opened and resealed without leaving visible evidence of entry.

The film wrapper must employ an identifying characteristic that cannot be readily duplicated. An identifying characteristic that is proprietary and different for each product size is recommended.

Tinted wrappers are no longer acceptable as an identifying characteristic because of the possibility that their material or a facsimile may be available to the public.

2. BLISTER or STRIP PACKS. Dosage units (e.g., tablets or capsules) are individually sealed in clear plastic or plastic compartments with foil or paper backing.

The individual compartment must be torn or broken to obtain the product. The backing materials cannot be separated from the blisters or replaced without leaving visible evidence of entry.

3. BUBBLE PACKS. The product and container are sealed in plastic and mounted in or on a display card. The plastic must be torn or broken to remove the product. The backing material cannot be separated from the plastic bubble or replaced without leaving visible evidence of entry.

4. HEAT SHRINK BANDS OR WRAPPERS. A band or wrapper is securely applied to a portion of the container, usually at the juncture of the cap and container. The band or wrapper is heat shrunk to provide a tight fit. The band or wrapper must be cut or torn to open the container and remove the product and cannot be worked off and reapplied without visible damage. The use of a perforated tear strip can enhance tamper-resistance.

Cellulose wet shrink seals are not acceptable. The knowledge to remove and reapply these seals without evidence of tampering is widespread.

The band or wrapper must employ an identifying characteristic that cannot be readily duplicated. An identifying characteristic that is proprietary and different for each product size is recommended.

Tinted bands or wrappers are no longer acceptable as an identifying characteristic because of the possibility that their material or a facsimile may be available to the public.

5. FOIL, PAPER, OR PLASTIC POUCHES. The product is enclosed in an individual pouch that must be torn or broken to obtain the product. The end seams of the pouches cannot be separated and resealed without showing visible evidence of entry.

6. CONTAINER MOUTH INNER SEALS. Paper, thermal plastic, plastic film, foil, or a combination thereof, is sealed to the mouth of a container (e.g., bottle) under the cap. The seal must be torn or broken to open the container and remove the product. The seal cannot be removed and reapplied without leaving visible evidence of entry. Seals applied by heat induction to plastic containers appear to offer a higher degree of tamper-resistance than those that depend on an adhesive to create the bond.

Polystyrene foam container mouth seals applied with pressure sensitive adhesive are no longer considered effective tamper-resistant features because they can be removed and reapplied in their original state with no visible evidence of entry.

The Agency recognizes that technological innovations may produce foam seals that will adhere to a container mouth in a manner that cannot be circumvented without visible evidence of entry. Container mouth seals must employ an identifying characteristic that cannot be readily duplicated. An identifying characteristic that is proprietary and different for each product size is recommended.

7. TAPE SEALS. Tape seals relying on an adhesive to bond them to the package are not capable of meeting the TRP requirements because they can be removed and reapplied with no visible evidence of entry.

However, the Agency recognizes that technological innovations may produce adhesives which do not permit the removal and reapplication of tape seals. In addition, tape seals may contain a feature that makes it readily apparent if the seals have been removed and reapplied. Tape seals must employ an identifying characteristic that cannot be readily duplicated.

8. BREAKABLE CAPS. The container (e.g., bottle) is sealed by a plastic or metal cap that either breaks away completely when removed from the container or leaves part of the cap attached to the container. The cap, or a portion thereof, must be broken in order to open the container and remove the product. The cap cannot be reapplied in its original state.

9. SEALED METAL TUBES OR PLASTIC BLIND-END HEAT-SEALED TUBES. The bottom of the tube is heat sealed and the mouth or blind-end must be punctured to obtain the product. A tube with a crimped end is capable of meeting the definition of a tamper-resistant feature if the crimped end cannot be breached by unfolding and refolding without visible evidence of entry.

10 SEALED CARTONS. Paperboard cartons sealed by gluing the end flaps are not capable of meting the TRP requirements. However, the Agency recognizes that technological advances may provide sealed paperboard packages that meet the requirements of the TRP regulations.

11 AEROSOL CONTAINERS. Aerosol containers are believed to be inherently tamper-resistant because of their design. Direct printing of the label on the container (e.g., lithographing), is preferred to using a paper label which could be removed and substituted.

12 CANS (BOTH ALL-METAL AND COMPOSITE). Cans may be composed of all metal or composite walls with metal tops and bottoms. The top and bottom of a composite can must be joined to the can walls in such a manner that they cannot be pulled apart and reassembled without visible evidence of entry. Rather than attaching a separate label, direct printing of the label onto the can (e.g., lithographing ) is preferred.

B. CAPSULE SEALING TECHNOLOGIES

Technologies for sealing two-piece hard gelatin capsules are available that provide evidence if the capsules have been tampered with after filling. Such sealing technologies currently in use include sonic welding, banding, and sealing techniques employing solvents and/or low temperature heating. These examples are not intended to rule out the development and use of other capsule sealing technologies. Manufacturers may consult with FDA if they are considering alternative capsule sealing processes.

Sealed capsules are not tamper-resistant packages. They are required to be contained within a package system that utilizes a minimum of one TRP feature.

C. TRP LABELING STATEMENT(S)

1. BOTTLE (CONTAINER) CAPS. In the past, some manufacturers have placed the TRP labeling statement on bottle caps. This practice is unacceptable in cases where it may be a simple matter to substitute another unlabeled bottle cap for the one with the tamper-resistant warning statement. Such an act could easily be accomplished without any apparent sign of tampering.

2. PACKAGE INSERTS. The practice of placing the TRP labeling statement solely on the product's inserts is not acceptable. While package inserts may be a useful supplement for consumer education purposes, they are not acceptable in lieu of label statements.

3. CARTON/CONTAINER (OUTER AND INNER). If the TRP feature is on an outer carton, the inner container (e.g., bottle) needs to bear a statement alerting the consumer that the bottle should be in a carton at the time of purchase. This policy applies only to situations where the inner container is so labeled that such a container might reasonably otherwise be displayed on the retail shelf without an outer carton.

4. IDENTIFYING CHARACTERISTIC. When a TRP feature is required to have an identifying characteristic, that characteristic needs to be referenced in the labeling statement (e.g., "imprinted" neck band). It is recommended that the labeling statement specifically identify the characteristic (e.g., imprinted with XYZ on the neck band).

5. TRP FEATURE(S). All required tamper-resistant features must be referenced in the labeling statement. When two tamper-resistant packaging features are used for unsealed two-piece hard gelatin capsules, both features must be referenced in the labeling statement. If one tamper-resistant packaging feature plus sealed capsules are used, the labeling statement must reference both the capsule seal and the tamper-resistant packaging feature.

REGULATORY ACTION GUIDANCE:

The TRP requirements are part of the current good manufacturing practice (GMP) regulations. Regulatory actions for deviations from these requirements should be handled in the same manner as any other deviation from the GMP regulations.

*Material between asterisks is new or revised*

Issued: 3/1/88
Revised: 5/21/92

Sec. 450.550 Control and Accountability of Labeling Associated with Tamper-Resistant Packaging of Over-the-Counter Drug Products (CPG 7132.14)

BACKGROUND:

Final rules (21 CFR 211.132) were published in the Federal Register on November 5, 1982 (47 FR 50442) (As corrected in 48 FR 1706) to provide tamper-resistant packaging requirements for certain OTC drug products.

Questions have been raised as to whether or not those parts of tamper-resistant packaging which may contain labeling, such as shrink seals imprinted with the product name, need to be controlled and reconciled, under the CGMP regulations. Questions have also been raised on the degree of control and accountability needed for parts of tamper-resistant packaging which may be part of the immediate container closure system or some other portion of the packaging.

POLICY:

Those portions of tamper resistant packaging which contain labeling, as defined in Section 201(m) of the FD&C Act, will be considered as any other labeling and, as such, are subject to the control and accountability provisions of Subpart G of the Current Good Manufacturing Practice Regulations.

Those portions of tamper-resistant packaging which contact the drug product are considered part of the container closure system and, as such, are subject to the control and accountability provisions of Subpart E of the CGMP regulations.

Those portions of tamper-resistant packaging which do not fall into the above categories will be considered as general packaging material, subject to the general controls for packaging contained in Subpart G of the CGMP regulations.

Issued: 3/1/83

Sec. 454.100 OTC Ear Drop Preparations (CPG 7132b.01)

BACKGROUND:

It has been our policy <> that the only acceptable claim for over-the-counter distribution of ear drops is for the loosening of wax. The inclusion of a local anesthetic agent in an ear drop whose primary function is to soften wax is irrational and may mask an acute infection.

REGULATORY ACTION GUIDANCE:

The following represents criteria for recommending legal action to the *Division of Drug Labeling Compliance, HFD-310*:

Any ear drop preparation offered for over-the-counter distribution that contains a local anesthetic

or

Any ear drop preparation offered for over-the-counter distribution with claims offering the product for conditions other than "for the loosening of wax."

REMARKS:

Some of these preparations may be suitable for marketing as prescription drugs.

*Material between asterisks is new or revised*

<> Indicates material has been deleted

Issued: 10/1/80
Revised: 5/22/87

Sec. 455.100 Inert Glandular Preparations *(OTC)*, Inadequate Full Disclosure and Claims (CPG 7132b.12)

BACKGROUND:

*When it was discovered that some glands produce hormones, a variety of glandular products were placed on the market for OTC medicinal use. Many of these commercial glandular preparations contained very little hormonal activity.

POLICY:

Our policy on inert glandular preparations is expressed in 21 CFR 201.300. It is our policy that inert glandular preparations intended for medicinal use are not exempt from Section 502(f)(1), that they bear adequate directions for use including indications for use and any such representations offering these articles for use as drugs would be false and misleading, and cause such articles to be unapproved new drugs*.

REGULATORY ACTION GUIDANCE:

The following represents criteria for recommending legal action to the *Division of Drug Labeling Compliance, HFD-310*.

Any desiccated whole or aqueous extracts of the following animal glands:

Adrena Orchic

Adrenal Cortex Parathyroid

Brain Parotid

Duodenum Pineal

Embryo Pituitary

Heart Placenta

Kidney Prostate

Liver Spleen

Lymph Stomach

Mammary Thymus

Ovary *Thyroid*

and

Such inert glandular preparation is offered for *OTC* drug use, other than, use limited to vitamin content in the case of liver preparations; use limited to intrinsic factor content in the case of stomach and duodenum, and parenteral use in the case of parathyroid.

*Material between asterisks is new or revised*

Issued: 10/1/80
Revised: 5/22/87

Sec. 456.100 Non-Rx Drugs Anti-Obesity Preparations <> (CPG 7132b.05)

POLICY:

We are not prepared to take regulatory action against the following class of products particularly those which have been on the market for a significant period of time:

Anti-obesity preparations containing phenylpropanolamine, methylcellulose, benzocaine, and related compounds, with or without vitamins offered only as an aid in reducing.

If the products contain other ingredients which would cause the drug to be dangerous to health when used as directed or if its labeling makes other claims we might wish to consider action. If you encounter such products which you believe warrant action, submit full labeling and formulation to the <> Division of Drug Labeling Compliance, *HFD-310* for advice before collecting samples for regulatory consideration.

*Material between asterisks is new or revised*

<> Indicates material has been deleted

Issued: 10/1/80
Revised: 5/22/87; 3/95

Sec. 457.100 Pangamic Acid and Pangamic Acid Products Unsafe for Food and Drug Use (CPG 7121.01)

BACKGROUND:

Pangamic acid has been promoted both as a dietary supplement and as a drug. Information available to us indicates that there has been no identity established for a substance characterized by the name pangamic acid (or "vitamin B-15"). The chemical structure and nature of such a substance has not been definitely determined. In addition, we are not aware of any accepted scientific evidence which establishes the nutritional properties of pangamic acid or which has identified a deficiency of this substance in man or animals. We are also unaware of a suitable specific analytical method for its determination. A similar product, containing a mixture of calcium gluconate and dimethyl glycene, has been promoted as the building blocks of "calcium pangamate," a salt of the so-called Vitamin B-15.

POLICY:

The Act defines the term "drug" in part as "... articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals ...." *Pangamic acid has historically been promoted as a treatment for cancer, along with other disease conditions.* If pangamic acid is offered for such purposes, it would be considered a drug and require clearance under the new drug provisions of the Act. Since pangamic acid has no approved new drug application it must also be considered a new drug without an approved new drug application.

REGULATORY ACTION GUIDANCE:

A. Domestic - Recommend legal action to *Division of Drug Labeling Compliance (HFD-310) on all pangamic acid products with accompanying labeling containing disease claims* (including products containing dimethyl glycine mixed with other compounds such as calcium gluconate) or on the manufacturer, packer, or distributor, in accordance with the following principles:

1. Seizure - Recommend open-ended seizures as the primary initial action against *manufacturers*, major repackers and distributors.

<>

2. Injunction - Recommended injunction

When follow-up to open-ended seizures reveals that a *manufacturer, major* repacker or distributor is continuing to distribute *pangamic acid labeled as drugs*. Injunction may be recommended by using established procedures or by amending the complaint for forfeiture, whichever is appropriate.

3. Criminal Contempt - Recommend criminal contempt when follow-up investigation reveals violation of the injunction.

SPECIMEN CHARGES:

<>

Drug Charge: The article is a drug within the meaning of 21 U.S.C. 321(p) which, pursuant to 21 U.S.C. 355(a), may not be introduced or delivered for introduction into interstates commerce since it is a "New Dug" within the meaning of 21 U.S.C. 321(p), and no approval of an application filed pursuant to 21 U.S.C. 355(b) is in effect for the drug.

B. Imports

Detain imports of pangamic acid products offered as a drug.

SPECIMEN CHARGES:

<>

Drug Charge: The article is violative within the meaning of 21 U.S.C. 381(a)(3) in that it appears to be a new drug within the meaning of 21 U.S.C. 321(p) for which no approval of an application filed pursuant to 21 U.S.C. 355(b) Is in effect for such drug.

NOTE: The regulatory action criteria do not apply to dimethyl glycine, when labeled as such and offered as a single ingredient compound for food use only.

***This CPG is Under Review***

*Material between asterisks is new or revised*

<> Indicates material has been deleted

Issued: 10/20/76
Reissued: 10/1/80
Revised: 9/1/83, 10/13/89, 3/95