Compounders Can Relax, But Not Too Much

By Douglas B. Farquhar –  

Drug compounders who are thinking about registering with FDA to become “outsourcing facilities” – and those 40 + that already have – will be interested in the details of FDA’s recent recognition that all of the rigid requirements for “current Good Manufacturing Practice” (cGMP) that apply to drug manufacturers are impractical for drug compounders that mix only small batches of product.  The bottom line of the draft Guidance issued by FDA earlier this week is that you can relax, but not too much.

And, in a commendable gesture of flexibility, FDA also asks outsourcing facilities and the public to comment on two alternative measures that could take some of the load off outsourcing facilities.  FDA asks for comments on proposals that would allow two types of companies– suppliers of components used in compounding and laboratories that test products for compounders – to register with FDA under the Drug Master File (DMF) process.  Then, when outsourcing facilities use DMF-registered components or have testing performed by DMF-registered laboratories, the outsourcing facilities are required to do less of their own testing.

You may remember that President Obama signed a law – the Drug Quality and Security Act (DQSA) – at the end of November 2013 that set up the new voluntary category of outsourcing facilities for those entities compounding sterile preparations for office use – sort of a “Drug Manufacturer Lite.”  We blogged on that here.  Traditional compounding pharmacies are, according to FDA and the newly reinvigorated FDCA Section 503A, prohibited from compounding drugs without a prescription for an individually identified patient.  The DQSA set up the new category of outsourcing facilities.  After registering with FDA, outsourcing facilities can compound sterile drugs without individual prescriptions.  Congress created the outsourcing facility designation to promote safer compounding practices for large-scale office use compounding of sterile preparations; used primarily to address drug shortages that keep patients and hospitals from getting access drugs they need, and for office stock compounding of those drugs on a yet-to-be-published “positive list.”  Restricting the type of drugs that can be compounded and the materials that can be used to compound them, the DQSA also requires that outsourcing facilities comply with cGMP, which FDA has defined in regulations governing traditional drug manufacturers.  The regulations are found in 21 C.F.R. Parts 210 and 211.

However, there are clearly some aspects of cGMP that simply are not practical for outsourcing facilities, which typically compound drugs in much smaller quantities (and yet compound a greater variety of preparations)  as traditional drug manufacturers.  Validation of the processes used to compound drugs, and the exacting stability testing that apply to each drug that is manufactured pursuant to drug approvals or FDA monographs simply won’t work when the maximum size of a lot of a drug product that is compounded is in the tens or hundreds (and frequently less), as opposed to the hundreds of thousands, or tens of millions.  Nor is full validation feasible when a drug shortage suddenly occurs.

So, while the FDA draft Guidance is not binding law, it sets forth FDA’s policy not to pursue outsourcing facilities that follow the Guidance’s somewhat less exacting standards on sterility testing and process validation.

Many of the standards governing facilities, environmental monitoring in sterile suites, gowning requirements for compounding personnel, labeling, and Quality Control/Assurance Units are identical to those for drug manufacturers.  Among other things, sterile drug manufacturing areas – either clean rooms or isolators (glove boxes) – must show unidirectional airflow under dynamic conditions, pressure differential between classified clean rooms must be monitored and alarmed, and environmental and personnel monitoring to detect particulates or other contaminants must be performed at least daily.  Sterilization and depyrogenation process must be validated, although (see page 7) outsourcing facilities can rely under certain circumstances on a certificate of analysis (COA) from a supplier for conformity with sterility of single-use containers, closures and equipment.  Bulk active ingredients and excipients can also be used based on a COA under appropriate circumstances (page 9).  But incoming testing of identity must be conducted on each lot of product received.

Here’s where FDA seeks comments: Instead of requiring every lot to be tested for identity, FDA wants to know whether people think it would work for the supplier to be registered with FDA under the DMF process, which is commonly used for ingredients of approved manufactured drugs.  The supplier would have to meet certain requirements in order to register with FDA, but that registration would take the testing requirement out of the hands of the outsourcing facilities.  Discuss among yourselves.

One area that has confounded compounding pharmacies is the requirement for sterility testing under the U.S. Pharmacopeia guidelines, which are the voluntary governing standards for some pharmacies and the state-imposed requirement for others.  The Guidance recognizes that the USP requirement of sterility testing on a minimum of four containers of product from a given lot or batch may be unreasonable.  So, the Guidance sets forth an alternative standard for batches of less than 100 containers:  Sterility testing only need be conducted on “a number of containers that equals 10%” of the lot “rounded up to the next whole number” (page 16).  Thanks, FDA.

On the next page, FDA then requests public comments on a DMF process for testing laboratories, that would take over much of the testing otherwise required to be performed in-house by outsourcing facilities.

Finally, and perhaps most importantly, the Guidance sets forth the standards for expiration dating (called the Beyond Use Date) for compounded sterile drugs.  The standards seem to replicate the USP requirements.

The Guidance is 21 pages, plus a list of sources and definitions, so this blogpost is not cannot pretend to be a comprehensive discussion of all its provisions.  We will keep you blogposted.