Are You Compounding or Manufacturing?
By Roger S. Klotz, R.Ph., BCNSP, FASCP, FACA, FCPhA, CDM
Recently a Medscape (August 11, 2006) electronic news update reported that the following, “FDA Warns 3 Pharmacies Against Mass Production of Compounded Drugs”. The US Food and Drug Administration (FDA) in August warned 3 pharmacies to cease their mass manufacture and nationwide distribution of unapproved compounded inhalation drugs used to treat asthma, emphysema, bronchitis, and cystic fibrosis. Because these products are not reviewed by the FDA for safety and efficacy and often not produced according to good manufacturing practice (GMP Standards) these products may expose patients to unnecessary risks according to an alert sent from MedWatch by the FDA.
The FDA indicated that the scale on which these medications are being compounded (millions of doses per year) suggests that FDA-approved, commercially available drugs are being copied, rather than modified to meet and individual patient’s special needs. The FDA has requested healthcare professionals report adverse events related to use of compounded drugs to the FDA’s MedWatch reporting program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, or online at http://www.fda.gov/medwatch .
The above information came from the article, “Deaths Spur Debate About Drugs Made in Pharmacies”, published in the USA Today. Compounding by pharmacists continues to raise concerns and the fact that the 3 companies were actually manufacturing and not compounding gets lost in the headlines. These organizations expose all pharmacists who are trying to provide quality care to negative press and increasing scrutiny by the FDA. Senator Grassley Chairman of the Committee on Finance has written a letter to Dr.Mark McClellan (Administrator of CMS) and Dr. Andrew C. von Eschenbach (Acting Commissioner of the FDA) regarding his concern over the compounding issue. He is concerned that the committee has received allegations that some pharmacies, in particular mail-order pharmacies and durable medical equipment (DME) suppliers may be producing and/or providing unsafe and/or ineffective or less effective nebulizer medications by inappropriately compounding prescription drugs. It appears that even the Senator is confused about the difference between compounding and manufacturing.
I have seen a number of pharmacists who unwittingly crossed over to manufacturing from compounding and thus exposed themselves to not only medical-legal risks, but also the risk of violating federal and state laws. I recently watched a pharmacist prepare a bulk container of albuterol and budesonide for inhalation. He prepared a liter of solution using sterile saline USP and adding non-sterile powders of the active and inactive ingredients. After assuring that the powders were fully mixed he removed the product from the ISO-5 hood and left the “Buffer Room”. When I asked him when he would sterilize (via filtration) the finished solution he said he would do that by the end of the week. This is a very high risk approach since time allows micro-organisms to grow. The life and death of micro-organisms result in the formation of pyrogens. Therefore, even if he did sterilize the product at the end of the week, any pyrogens (since they are soluble and heat stable) will be in the solution. Fortunately, this product was not going to be used intravenously, but it does show that there are individuals taking enormous legal and medical-legal risks without fully understanding what they are doing. This pharmacist had not only crossed over to be a manufacturer, but he was at high risk of producing a contaminated product which could put his patients at risk. This is exactly what consumers, congress, and therefore the FDA is concerned about.
The American Academy of Allergy, Asthma, and Immunology and the American College of Allergy, Asthma, and Immunology proposed a resolution to the above problems by urging the AMA to request that the FDA take enforcement action against pharmacies that are mass manufacturing medications under the guise of compounding and that CMS reconsider paying for these medications. As a result CMS is looking at the whole reimbursement for inhalation medications to address the manufacturing of inhalation drugs by pharmacies. One approach that is being considered is moving the reimbursement for inhalation medications from Part B to restricting it to Part D so that only manufacturer’s products will be reimbursed. The other approach being considered is to require accreditation of all compounding (sterile and non-sterile) pharmacies in order to obtain Medicare reimbursement for medications.
When I was with Home Health Care of America – Caremark we compounded TPN prescriptions using non-sterile powder amino acids, electrolytes, glucose, and trace elements in a bulk method since we would make a number of bags for the patient. The solutions were sterilized through a 0.22 micron filter as the sterile bag was being filled. To do this though, we developed in depth quality control including certification of origin for all ingredients to assure purity and assure that the ingredients were pyrogen free. All filters went through “Bulb Point” testing after filling and one of the produced bags was used to test each patient’s prescription for sterility and assure they were pyrogen free. This was done as part of the process. We also obtained experienced legal opinion to assure that we did not cross over to manufacturing and thus be at legal risk. At one point the FDA did survey 5 of our branches to see if we were manufacturing and so did we meet GMP (Good Manufacturing Practices) standards if we were manufacturing. The final report to FDA headquarters was that we were compounding patient specific prescriptions under the direction of their physician so we were practicing pharmacy. They did indicate that we were meeting GMP standards and therefore we could get a license from the FDA as a manufacturer. Our organization decided though to continue to practice pharmacy.
There is a tremendous difference between manufacturing and compounding. Manufacturing basically is producing product whose use will eventually be used and supervised by a healthcare professional. The manufacturer does not deal with specific patients and has no specific patient information, but only produces bulk product. They have no idea who will receive the product or who will really be supervising its use other than the fact that licensed professionals will be involved. Manufacturing is not patient focused, but is product focused. Compounding on the other hand must be patient focused since the whole concept is to compound prescriptions designed for a specific patient with specific physiological processes and a specific disease process that is specific to that patient. Therefore, there are some key points required for compounding that are not required for manufacturing just as the reverse is true. It is critical that the compounding pharmacist and his organization understand the difference and avoid becoming a manufacturer since this puts the patient at very high risk. The compounding pharmacist must understand the medical, pharmacological, pharmacokinetic, pharmacogenomic, and physiological need of each of his/her patients. The compounding pharmacist must not only know each of his/her patients, but they must know each of the patient’s diagnostician to assure that all of the patient needs are being considered so the proper finished dose can be compounded. Manufacturing is a technical function done by technicians, while compounding is a professional function that must consider the needs of each individual patient separately from all other patients.
Some basic rules for a compounding pharmacist (based on legal opinion) are that:
- The pharmacist, patient, and physician triangle must exist. The pharmacist works directly with the patient’s physician and provides services directly to the patient without an intermediate.
- There is no bulk compounding which is shipped to an intermediate for sale/distribution.
- The prescription is a patient specific dose and/or contains tailored ingredients (i.e. special preservatives, special vehicle) for the specific patient.
- They must have a full understanding of the patient’s clinical status, disease process, and special needs. This information is obtained and documented by working with the specific patient/caregiver and their physician.
- The pharmacist must complete a patient specific care plan which is continually updated.
- The pharmacist must have appropriate specific compounding policies and procedures that direct patient specific compounding.
- The pharmacist compounding policies and procedures must address their quality assurance and quality improvement program.
Remember pharmaceutical manufacturers are product oriented, as they should be, while the compounding pharmacist and their organization must be patient focused. I would suggested that if you are unsure as to where your organization stands that you seek professional consultation (i.e. technical, clinical, legal) to assure that you are addressing the appropriate standards and you are truly a compounding pharmacy. If you are going to bulk produce products then you should get a consultant to help you address GMP standards and apply with the FDA for the appropriate manufacture’s license. You can not be both, but you must decide as to which you will do. Will you do patient specific compounding working with the patient’s physician or will you be a manufacturer of products.