process did you go through in determining that it would be possible for you to make a pill which would work? Mr. MILLER. Our technician, the head of our research and production, Dr. Ibert Mellen, quite an eminent chemist, conducted experiments. He was satisfied that we could produce the pill as required to meet the specifications. Mr. BROWNSON. Were these experiments accomplished between the time you received the invitation to bid and the time you responded with your bid offer? Mr. MILLER. I believe these experiments were conducted even earlier. Hexylresorcinol pills, or tablets as we made them, had appeared in Government bidding over a period of time. I believe awards were made to the Cowley Manufacturing Co. in Massachusetts on hexylresorcinol pills or tablets, and I believe another firm named Fine Organics, in New York City, had supplied hexylresorcinol pills or tablets to either the GSA or the armed services. Since we were manufacturing tablets it occurred to us that we might be able to produce a satisfactory tablet and we went to work on it. Mr. BROWNSON. Do your cost sheets indicate you utilized any gelatin in your coating? Mr. MILLER. Yes, sir; it does. Mr. BROWNSON. Will you give the subcommittee a list of the materials entering into your hexylresorcinol coating and whether your product contains an inner sealing? Mr. MILLER. Gelatin, the dye, chalk, sugar, talc, and stearic acid. The process these tablets went through was devised by Dr. Mellen. I would have to defer to him as to any procedures. Mr. BROWNSON. Is there any formaldehyde in that coating? Mr. MILLER. May I refer to a file here which covers formaldehyde in one of those shipments? Mr. BROWNSON. Will you please? Mr. MILLER. May I read a letter which was written on July 27, 1953, addressed to Mr. J. W. Peed, of the GSA, Washington, D. C.? Mr. BROWNSON. Will you please? Mr. MILLER. I will quote part of it concerning this. We have manufacured for the commitments and we have offered for delivery perfectly good suitable tablets in conformity with our contracts and as required by the U. S. P. The coating on our tablets does not tend to crack under pressure and is quite flexible. The coating on our tablets does conform to the U. S. P. requirement of "a tough gelatin coating." While it is true that our tablets have a slight formaldehyde odor when first made, this disappears in a few days. Formaldehyde is used to make a tough gelatin coat (see references below), and our tablets have no odor of formaldehyde upon standing for several days. The Dispensatory of the United States, page 1178, lines 26 to 30, states, re formaldehyde-treated gelatin, the so-called glutoid coatings, were prepared by coating tablets or pills with gelatin, then rendering the latter acid insoluble by dipping into dilute solution of formaldehyde. Remington's practice of pharmacy, 1948, Cook-Martin, page 678, under hexylresorcinol pills, U. S. P., states "hexylresorcinol pills contain crystaline hexylresorcinol and are covered with a tough gelatin coating." Tough gelatin capsules are the socalled glutoid capsules, page 312, lines 11 to 15. Another form is the so-called glutoid capsules. These are prepared by subjecting hard or soft capsules containing the medication and carefully sealed to the action of formaldehyde until they become insoluble in the stomach, but retain their solubility in the intestine. That is the reference to formaldehyde. Mr. BROWNSON. Does your product contain an inner seal which contains the hexylresorcinol to protect the coating from it? Mr. MILLER. That seal is made in the application of the gelatin. As I understand the procedure and the process, there are coatings upon coatings put on to these tablets until the outer coating becomes strong enough to resist pressure. Mr. JUDD. That still doesn't answer the question. Formaldehyde makes an outer seal. It hardens the outside layer of gelatin. That is why you contend it is not dangerous because it is used only to corrode to harden-the outside layer. Then after it is hardened the formaldehyde is rubbed off, or it evaporates. That doesn't deal with the inner seal. Mr. MILLER. I will have to defer to our Dr. Mellen on that, sir. Mr. BROWNSON. Is he here in the room? Mr. MILLER. No. He was not asked to come down. Mr. BROWNSON. Would you be kind enough to supply that information from your technical department? Mr. MILLER. Indeed. Mr. BROWNSON. Is there an inner seal immediately surrounding the hexylresorcinol material? The Sharp & Dohme people testified that in their process they took the hexylresorcinol material and then put on a subcoating which had a tendency to protect the gelatin from the hexylresorcinol. Mr. MILLER. All right, sir. Mr. JUDD. Someone has said these were examined and didn't contain gelatin. Was that the Food and Drug Administration? Mr. BROWNSON. That was Sharp & Dohme's laboratory analysis. Mr. JUDD. I see where Food and Drug reported they were not satisfactory. Somebody testified that they were not satisfactory, but I wondered if it was on the basis of the drug inside or the coating. Mr. WILLIAMS. The coating was described as brittle. Mr. BROWNSON. One of the Food and Drug examinations, which I have before me, failed to reveal gelatin. Mr. JUDD. That is what I saw somewhere. Mr. BROWNSON. This is the examination of March 27, 1953. It states: Analysis has been completed on a sample identified as follows then it lists the sample in the contract— the product fails to comply with USP requirements for assay. USP requires that hexylrescorcinol pills contain not less than 91 percent and not more thanMr. MILLER. 109, sir. Mr. BROWNSON (continues reading): 109 percent of the labeled amount of the hexylresorcinol. Our examination shows not more than 85.6 percent of the labeled amount. The USP further requires that hexylresorcinol pills be covered with a tough gelatin coating. The pills apparently do not conform in this respect. Our Washington laboratories also failed to get a positive test for gelatin in the coated pill. Incidental to the above examination our Washington laboratories noted that the pills were quite resistant to synthetic gastric juice as well as to saturated sodium carbonate solutions. They consequently wondered if the pills could be absorbed after ingestion. Some of the pills were given orally to dogs, and it was found that they were apparently disintegrated and absorbed. Mr. MILLER. Might I reply to that, sir? Mr. BROWNSON. Yes. Mr. MILLER. Our reply is dated April 3, and it is written to the United States Food and Drug Administration, 201 Varick Street, New York. Mr. BROWNSON. Excuse me just a moment. I would like to ask unanimous consent that the letter I have just read from be included as exhibit No. 30 and that the letter which Mr. Miller is about to read be included as exhibit No. 31. Mr. GLADSTONE. Would you want us to include a photostatic copy? Mr. BROWNSON. Yes. (Exhibits 30 and 31 are as follows:) T-NY-541 Hexylresorcinol Pills Mr. S. G. MORGAN, EXHIBIT 30 RETORT PHARMACEUTICAL CO., INC., Chief, General Services Administration, Inspection Division, Federal Suply Service, 250 Hudson Street, New York 13, N. Y. DEAR SIR: Analysis has been completed on a sample identified as follows: Contract: GS-03P-65 (EC) Lot No.: K2-2292A Product fails to comply with USP requirements for assay. The USP requires that Hexylresorcinol Pills contain not less than 91 percent and not more than 109 percent of the labeled amount of Hexylresorcinol. Our examination shows not more than 85.6 percent of the labeled amount. The USP further requires that Hexylresorcinol Pills be covered with a tough gelatin coating. The pills apparently do not conform in this regard. Our Washington laboratories also failed to get a positive test for gelatin in the coated pills. Incidental to the above examinations, our Washington laboratories noted that the pills were quite resistant to synthetic gastric juice as well as to saturated sodium carbonate solutions. They consequently wondered if the pills would be absorbed after ingestion. Some of the pills were given orally to dogs, and it was found that they were apparently disintegrated and absorbed. Very truly yours, F. C. SINTON, Acting Chief, New York District. Enclosures-6 copies this letter (with 2 copies Form 84 (2)). EXHIBIT 31 APRIL 3, 1953. Re General Services Administration Federal Supply Service, 250 Hudson St., 201 Varick St., New York, N. Y. (Attention Mr. F. Sinton.) GENTLEMEN: With the permission of the General Services Administration's New York office, we have attempted to contact you today by telephone, to discuss the testings and methods of analysis in regard to the material outlined in the above referenced report. Since you are unavailable, we take this opportunity to write to you as follows: The lot, from which the above mentioned Hexylresorcinol sample pills were taken, was assayed and found to be within the requirements of the U. S. P. Our assays were made on the original Hexylresorcinol powder; assay on the granulation; assay on the uncoated pill, and the last assay, on the finally completed coated pill. In the last, we find that Hexylresorcinol particles do tend to cling to the gelatin coating, and this could be overcome only by triturating with methanol and allowing the crushed pills to stand in intimate contact with the meth anol for at least 3 hours before filtering. We have found further, in our laboratory testings, that the end point is fluctuating and difficult to ascertain without considerable comparative testing. Using a pure grade of Hexylresorcinol as a 100 percent reference standard, we have determined that the end point should be taken at the first decolorization of starch. Should your laboratory be following this procedure, we believe that they will find our pills within the U. S. P. limits. In regard to the paragraph concerning the gelatin coating, we advise herewith that gelatin is definitely inserted into the coating material. In fact, we have been using Swift's Viscomix U. S. P. brand, which is the best and most expensive available gelatin. May we suggest that perhaps your laboratory's testing for gelatin is not sufficiently sensitive? We know that the gelatin is definitely used, and our laboratory conclusively confirms this in their tests. This can best be ascertained by removing the coating before testing. May we please recommend that our above suggestions as outlined herein, be taken into account in a retesting of the pills in your possession? Very sincerely yours, cc: GSA-Attn: Mr. Tall. LH: rm. Mr. MILLER (reading): RETORT PHARMACEUTICAL CO., INC., United States Drug Administration, 201 Varick Street, New York, April 3, 1953. With the permission of the General Services Administration New York office, we have attempted to contact you today by telephone to discuss the testings and method of analysis with regard to the material outlined in the above reference report. Since you are unavailable we take this opportunity to write you as follows: The lot from which the above-mentioned hexylresorcinol sample pills were taken was assayed and found to be within the requirements of the USP. Our assays were made on the original hexylresorcinol powder, assay on the granulation, assay on the uncoated pill, and the last assay on the finally completely coated pill. In the last, we find that hexylresorcinol particles do tend to cling to the gelatin coating, and this could be overcome only by triturating with methanol and allowing the crushed pills to stand in intimate contact with the methanol for at least 3 hours before filtering. We have found further in our laboratory testing that the end point is fluctuating and difficult to ascertain without considerable comparative testing. Using a pure grade of hexylresorcinol as a 100 percent reference standard, we have determined that the end point should be taken at the first discoloration of starch. Should your laboratory be following this procedure we believe that they will find our pills within the USP limits. In regard to the paragraph concerning gelatin coating we advise herewith that gelatin definitely is inserted into the coating material. In fact we have been using Swift's Visco Mix, USP brand, which is the best and most expensive available gelatin. May we suggest that perhaps your laboratory testing for gelatin is not sufficiently sensitive? We know that the gelatin is definitely used, and our laboratory conclusively confirms this in their tests. This can best be ascertained by removing the coating before testing. Mr. JUDD. What do you mean, not sensitive enough? You mean not sensitive enough to detect the minute quantities? Mr. MILLER. No, not sensitive enough in their tests. Mr. JUDD. Well, they test for gelatin. It shows it if it is there. Mr. MILLER. We found gelatin. We put gelatin on to the coating and found gelatin in every tablet we made. Mr. JUDD. Why wouldn't they have found it? Mr. MILLER. We questioned their methods. They must have found gelatin on our tablets because they tested for the USP test and they wouldn't release our shipments until they passed them. Mr. BROWNSON. We included in the record previously exhibits 13, 14, and 15 dealing with the gelatin coating, and all of them signed by Mr. F. C. Sinton, Acting Chief, New York District. 55430-54-6 Because those already have been included I would like to include as exhibit 32 a letter from the Retort Pharmaceutical Co. under date of July 27, 1953, in defense of the quality of the gelatin coating and pertaining to the three reports. (Exhibit 32 is as follows:) EXHIBIT 32 JULY 27, 1953. Re Contracts-Hexylresorcinol tablets GS-03P-65 (EC)-4,080 vials x 5 tablets. GS-03P-287 (EC)-30,000 vials x 5 tablets. Mr. J. W. PEED, Federal Supply Service, General Services Administration, 7th and D Streets SW., Washington 25, D. C. DEAR SIR: In reply to your telegram of July 20, 1953, concerning the abovereferenced contracts, we wish to advise that we do not believe ourselves in default and herewith request that our right to deliver be reasonably considered and fulfillment of the contracts be permitted as contracted. We have manufactured for the commitments, and we have offered for delivery, perfectly good, suitable tablets, in conformity with our contracts and as required by the USP. The coating on our tablets does not tend to crack under pressure and is quite flexible. The coating on our tablets does conform to the USP requirement of a "tough gelatin coating." While it is true that our tablets have a slight formaldehyde odor when first made, this disappears in a few days. Formaldehyde is used to make a tough gelatin coat (see references below) and our tablets have no odor of formaldehyde upon standing for several days. The Dispensatory of the United States-Closol-Farrar : page 1178, lines 26 to 30: "Formaldehyde-treated gelatin, the so-called glutoid, coatings were prepared by coating tablets or pills with gelatin, then rendering the latter acid-insoluble by dipping into dilute solution of formaldehyde." Remington's Practice of Pharmacy (1948)-Cook-Martin: page 678-under Hexylresorcinol Pills USP: "Hexylresorcinol Pills contain crystallin hexylresorcinol and are covered with a tough gelatin coating." Tough gelatin capsules or the so-called glutoid capsules, page 312-lines 11 to 15: "Another form is the so-called glutoid capsules. These are prepared by subjecting hard or soft capsules, containing the medication and carefully sealed, to the action of formaldehyde until they become insoluble in the stomach, but retain their solubility in the intestine." After receiving your telegram we contacted Mr. Sinton of the Food and Drug Administration in New York. This matter was discussed. However, he could only refer us to Dr. Frank H. Wiley of the Food and Drug Administration in Washington. He also stated there were no comparable means of testing, and that the present USP does not require or supply a specific measure for testing pressure or toughness. Dr. Wiley primarily resorted to Webster's Dictionary for the professional definition of the word "tough" (as required in the USP). He could only then refer us to Dr. Miller of the United States Pharmacopoeia in New York City. Dr. Miller reiterated that the present edition of the USP does not provide for any requirement for testing the degree of pressure or toughness of Hexylresorcinal Pills. These gentlemen have therefore confirmed to us our sincere belief that our tablets are in full accord with the USP. We have conducted our tests, handling the complete tablet-the coating and the inner Hexylresorcinal content, as one single unit, and we find these complete tablets to be tough. (Incidentally, Dr. Wiley advised that their tests were conducted by removing the coating from the core. Dr. Miller agrees with out contention that this is not a fair test, for we are supplying a complete unit and therefore tests must be conducted accordingly. We repeat, as a unit the tablet coating is tough and flexible.) Dr. Wiley's chief objection is based on Webster's definition of "tough"-"strong or firm in texture but flexible and not brittle," but he has refused to look at the many other meanings defined in Webster's Dictionary-"not easily chewed and or masticated; glutinous; sticky; stiff; vigorous," etc. We again bring to your attention that if we must resort to Webster's Dictionary for professionally technical applications, please note Webster's additional definitions. Our tablets' toughness meet all these definitions in every respect. |