Compounding Pharmacies’ Observations Correlate With Those From Large Pharma ISO 5 Facilities

Compounding pharmacies continue to receive citations from the FDA (both Form FDA 483s and Warning Letters) for a continuing failure to meet 21 CFR 210/211 requirements.  All one needs to do is visit FDA’s Electronic Reading Room to learn of the ORA audits and the subsequent citations.  Even after the New England Compounding Center issues that resulted in both death and injury, these compounding centers have continued to operate and, now not only have had initial visits, but subsequent visits as well as received both 483s and Warning Letters.

Roy Sturgeon, PhD, Lachman Consultant Services, recently posted several Blogs (Click on Blogs) regarding this lack of compliance and has provided a list of the “Top Ten” most frequently cited FDA observations.  If one would compare this list to any list of observations from a large pharm ISO Class 5 aseptic filling operation, one would note how similar each is to the other.  These include:

1. “Inadequate or lack of environmental monitoring of facility and people
2. Inadequate laboratory procedures and controls (definition of a “batch”, sampling and testing controls)
3. Lack of Standard Operating Procedures to prevent microbial contamination
4. Inadequate deviation/variance controls and lack of adequate investigation
5. Stability program nonexistent or does not support beyond use dating
6. Validation of final sterilization (filter or terminal), media fill design
7. Inadequate cleaning and disinfecting programs
8. Batch release (most done at risk or with no testing for sterility, potency, identity, and pyrogens)
9. Control of equipment (preventive maintenance and calibration program inadequate or nonexistent)
10. Inadequate facilities designs and controls, inadequate smoke studies”

“The top ten are now followed by: Lack of validated analytical methods for stability and potency testing, lack of analytical methods for determining impurities and extraneous peaks in chromatography, personnel qualifications, training and skill maintenance, no segregation of beta lactams for other preparations, ineffective quality unit, labeling matters, personnel not trained in GMPS, change control, incoming supplies acquisition and approval, inadequate raw material controls, inadequate separation of operations, record keeping, and inadequate SOPs for operations, environment that poses a significant contamination risk.”

A recent example of a Warning Letter was issued to Oregon Compounding Center, Inc. (Click Here) that illustrates the similarity between the summary of Dr. Sturgeon and the Warning Letters that continue to be issued.  The FDA indicated that they had issued a Form FDA-483 to the facility on August 28, 2014, and issued as an amended Form FDA-483 on September 12, 2014.  A Warning Letter was subsequently issued on January 27, 2015.  An extensive list of FDA 483s, Warning Letters and Recalls relating to Compounding Centers may be found .  Within the Warning Letter many of the same elements were noted as within the “Top Ten” most frequently cited FDA observations.  These include:

1. Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)).

2. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

3. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)).

4. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

5. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

6. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

The FDA further states the Company should:

“Please be aware that section 501(a)(2)(A) of the FDCA concerning insanitary conditions applies regardless of whether the drugs are compounded and distributed after receipt of a prescription for an identified individual patient. In addition, should you manufacture and distribute domperidone drug products or drug products without valid prescriptions for individually-identified patients, the manufacture of such drugs would be subject to FDA’s drug CGMP regulations (21 CFR Parts 210 and 211), among other requirements described above, and, before doing so, you should fully implement corrections that meet the minimum requirements of 21 CFR Part 211 in order to provide assurance that the drug product(s) produced by your firm conform to the basic quality standards that ensure safety, identity, strength, quality, and purity.

FDA strongly recommends your management immediately undertake a comprehensive assessment of your operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess your aseptic processing operations.”

Just because a Company is not a multi-national biopharmaceutical and only performs compounding does not make it exempt from following 21 CFR 210/211.