The opinion of the court was delivered by: CARTER
The Proceedings and Parties' Contentions
These proceedings for forfeiture were instituted on June 1, 1976, pursuant to the provisions of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 301 et seq., with the filing of a complaint for the destruction and condemnation of certain specified lots of a drug named colchicine, and various lots of a drug called dihycon diphenylhydantoin, manufactured by Barr Laboratories, Inc. and by Ormont Drug & Chemical Co., respectively and repackaged by claimant, Consolidated Midland Corporation preparatory for shipment and distribution in interstate commerce. Pursuant to a warrant issued by this court, the articles were seized by United States Marshals on June 18, 1976, as authorized by 21 U.S.C. § 334(a)(1). Consolidated filed a claim for the seized articles and an answer to the complaint in August, 1976.
The complaint alleges that the claimant has introduced the affected drugs (dihycon diphenylhydantoin and colchicine) into interstate commerce in violation of 21 U.S.C. § 355. The complaint further alleges that certain lots of colchicine and dihycon phenytoin are mislabeled and misbranded; that the claimant failed to conform to current good manufacturing practice as required and concretized by regulations promulgated by the Secretary and set out at 21 C.F.R.§ 200.31 and §§ 211.1 through 211.115 in respect of the processing, packaging, labeling or holding of the affected articles to insure that the statutory and regulatory requirements as to safety, identity, strength, quality and purity characteristics are met; and that hence the drugs are adulterated and misbranded within the meaning of 21 U.S.C. § 351(a)(B).
Defendant claims that it is not in violation of 21 U.S.C. § 355 because its dihycon was in commercial use before the 1962 amendments to the Food, Drug & Cosmetic Act and accordingly that the drug is grandfathered and exempt from compliance with § 355; that while there may be evidence of technical deviations from current good manufacturing practice, there has been no showing that these deviations affected in any way the safety or other characteristics of its colchicine and dihycon; and that the alleged misbranding was a pure, minor technical violation, since even though labeled "100 capsules," the packets in question were transparent and clearly revealed the actual number of capsules therein.
The case was tried to the court on May 24-May 27, 1977. The filing of post trial proposed findings, conclusions and memoranda was completed on November 9, and the exhibits were submitted to the court on November 23.
Prior to the institution of these proceedings Frederick Lochner, an inspector for FDA, made an inspection of claimant's plant. He was given claimant's Standard Operating Procedure (SOP) designed to verify that claimant's processing, packaging, handling and labeling of its articles conform to good manufacturing practice. He found that the SOP was in draft form only; shipments were made without a notation thereof being recorded on the product's invoices, part of the lot numbers were missing from some labels, and claimant's address was incorrectly listed on some labels. The protocol assay relied on as insuring the identity, stability and quality of the dihycon drug was four years old and inadequate on its face, but no new tests had been taken by the claimant. Articles were repackaged from lots before examination, identification or receipt of assays, and distributed without analysis being performed by the packager to insure the identity and quality of the article. Quality control procedures were not scrupulously adhered to. While the SOP itself seems to require that good manufacturing practice be followed, the practices actually in operation were such that the claimant would be unable to verify that the SOP was in fact followed in the processing, repackaging and handling of the articles. Labeling procedures were such that the identification, history and manufacture of the batch from which the finished product was repackaged and labeled could not be validated. The claimant was unable to supply the inspector with stability data as to the affected articles. Lots of the affected articles had been held for long periods and repackaged without testing to assure that there had been no deterioration in strength or quality. There were 42 packet lots of dihycon diphenylhydantoin, each identified as containing 100 capsules, but actually each contained only six capsules. This testimony stands virtually uncontroverted and is accepted and adopted as part of the court's findings.
Dr. Murray Tuckerman, Professor of Pharmaceutical Economics and Health Care Delivery at Temple University, testified that everything the firm does from receipt of the material until it is shipped from the plant should be listed on the SOP, and the reason and purpose for doing this is to insure that a safe and effective product leaves the plant. SOP saves the company from being required to give specific and separate instructions to each employee each time the material is handled. While there is flexibility in re the form of the SOP, it should be complete and indicate how the material is to be received and processed, what records are to be kept, what is to be done with the records under various contingencies, what must be done to release the material, who has responsibility for what, what are the procedures in the packaging process, what examinations are to be undertaken prior to the materials' release and under what conditions will release be withheld. He considered the SOP here deficient because no procedures are required to enable management to confirm that what is set out in the SOP as a requirement is operationally accomplished. Articles of drugs were repackaged from lots on receipt by Consolidated and before any examination or identification of the drugs by Consolidated personnel and before any receipt of protocols of assay. The drugs were distributed without Consolidated having on hand either an analysis of the product from the manufacturer and/or an analysis being made by Consolidated itself, and lots of the drugs were repackaged prior to being released by quality control for that purpose. Consolidated's labeling operations do not require procedures to insure identification of the labeled products with any specified lot or controls that would permit a determination of the history of the processing and manufacture of the labeled batch.
Dr. Harold Booker, a neurologist, on the faculty of the Department of Neurology in the School of Medicine of the University of Wiscosin, testified for the government. For the past 12 years his exclusive professional activity has been the diagnosis and treatment of epilepsy along with research in the use of drugs in the treatment of that disorder. He has treated some 2,000 epilepsy patients with phenytoin. Since the rate of absorption of different brands of phenytoin varies, he has found it best if a patient becomes stabilized on one brand, not to change to another. Because there are various undesirable side effects from use of the drug, Dr. Booker's practice and recommendation is that only the minimum amount of phenytoin that will suffice to prevent epileptic seizures in the particular patient should be administered. Among these side effects are overgrowth of gums, stimulation of the growth of body hair, interference with the functioning of Vitamins D and K, and formation of folic acid. He does not use or prescribe the use of dihycon which is the only time release phenytoin he is familiar with because he is unaware of any data establishing its absorption characteristics, which he regards as critical. Without such established data, he does not regard dihycon as safe and effective for use under the conditions prescribed.
Dr. Richard Gural, an FDA administrator and pharmacokinetist, was also a government witness. His FDA function is to evaluate data submitted to the agency to document the effectiveness and safety of a drug intended for marketing. He received a submission by Consolidated re dihycon. In evaluating a drug, he applies a series of mathematical equations to the time course of the drug in the blood stream to determine its rate of absorption, distribution, metabolism and excretion. He stated that an abbreviated new drug application does not necessitate the extensive data required of a new drug application because the abbreviated new drug application seeks approval for marketing a drug that is the same or the equivalent to one already on the market. With such application a bioequivalency study should be done comparing the new drug with the old one already on the market. He concluded that Consolidated's submission did not establish that its dihycon was safe and effective on the basis of bioequivalency and bioavailability data (rate of the drugs' absorption and availability at drug site) in respect of dilantin, a single dosage form of phenytoin now on the market.
Charles Peppinger, a clinical pharmacologist and an Assistant Professor of Neuropharmacology at the College of Physicians and Surgeons of Columbia University, testified that he had worked for some 15 years with phenytoin in the treatment of epilepsy. He had undertaken the study of time release phenytoin by switching patients on single does dilantin to a time release preparation. The patients began having seizures, and he concluded that the drug was not safe and effective for the relief of epilepsy.
Consolidated's expert Dr. Alexandra Feldmann, a practicing physician from Rochester, testified that over the past ten years she had used dihycon on what she estimated to be roughly 200-250 of her patients with good results. Robert Goldman, a pharmaceutical chemist, testified that his employer NYSCO Laboratories had manufactured phenytoin in time release form in the 1950's and had manufactured this drug for Consolidated in the late 1950's and earlier. Jaap Ketting, claimant's President, testified that Consolidated had purchased time release phenytoin from NYSCO Laboratories from 1959 until 1972 when the premises were closed. Since that time another pharmaceutical manufacturer has supplied them with the drug manufactured under the NYSCO formula.
There was no testimony by any of the experts for the claimant or the government that there was in existence and available any body of literature or other documentary source attesting to the safety and effectiveness of time release ...