Date: Mar 14, 1998
FDA has focused substantial resources on upgrading
pharmaceutical industry compliance with good manufacturing
practice (GMP) over the past few years. Two enforcement actions
in recent years have clearly boosted FDA's confidence in GMP
cases. In an enforcement action against Warner Lambert, the
company was forced to close all of its facilities and consent to
FDA approved audits before recommencing operations. FDA won that
showdown without actually having to litigate any of its GMP
interpretations. In contrast, an enforcement action against Barr
Laboratories proceeded to a court decision as Barr went the
distance in trying to establish that its implementation of GMP
was adequate. See U.S. v. Barr Labs, 812 F.Supp. 458
(D.N.J. 1993). The opinion provides a strong endorsement for
FDA's conservative approach to the need to validate sampling
plans and for all manufacturing decisions to be founded on
soundly documented investigations.
A clear message having been sent to the finished
pharmaceutical manufacturers, it appears that FDA is now turning
its attention increasingly toward bulk suppliers. Facilities that
have had favorable inspections over the years are now
experiencing inspections with long lists of discrepancies. While
most of the observations relate to the need for improved
documentation and procedures, some have questioned long-standing
procedures that will be costly to upgrade. As part of its ongoing
program, FDA has released a revised draft of its Guidance for
Industry--Manufacturing, Processing, or Holding Active
Pharmaceutical Ingredients (dated April 18, 1998, and
available at http://www.fda.gov/cder/guidance/index.htm).
This document follows up on a "discussion draft"
released in September 1996.
FDA's authority to inspect manufacturers of active
pharmaceutical ingredients (APIs) and to enforce GMPs by such
establishments is not in question. Until FDA released the
discussion draft cited above, however, the most relevant document
that FDA had made available was entitled FDA Guide to
Inspection of Bulk Pharmaceutical Chemicals. This guide was
directed toward FDA's own inspectors. It made clear that bulk
operations were different from finished dosage preparation and
that more leeway was appropriate in inspecting such facilities.
The codified GMPs at 21 C.F.R. Parts 210 and 211 (for finished
dosage forms) were identified as an appropriate guide,
particularly for final manufacturing steps that should be at the
level of GMP required for finished pharmaceuticals. While that
general message still gets lip service, the details have changed
considerably. It appears that the recordkeeping expectations for
a finished pharmaceutical manufacturer are being applied to all
stages of bulk production.
One provision that may be particularly troublesome for bulk
manufacturers is the need to use potable water, at a minimum,
even for the early stages of production--with more stringent
water requirements for latter stages. While water quality is an
important issue, the reaction and processing conditions involved
in many bulk operations are such that the time and money spent to
achieve potable water quality before the water enters the bulk
process is money down the drain.
The revised draft has some adverse implications with regard to
storage requirements. It notes that a written program for
stability testing should be followed that includes defined and
controlled storage conditions specified on the label for the
marketed product (e.g., temperature and humidity). In particular,
FDA notes that "[w]here applicable, labeled storage
conditions should comply with standard definitions for 'Freezer,'
'Cold,' or 'Controlled Room Temperature,' as defined in the
United States Pharmacopeia (USP)" or ICH guidelines. Large
warehouses are unlikely to have adequate conditioned air to be
API manufacturers should continue to evaluate their GMP
compliance status in light of the revised API draft and be
prepared with sound science-based support for continuing any
practices that are not sanctioned. Manufacturers of excipients
should also pay heed to this document since FDA notes that
"much of the guidance provided [also] may be useful to the
manufacturers of excipients."
For more information on this subject please contact Frederick A. Stearns at 202-434-4288