is Vice President of Excellent Pharma Consulting, Inc. 404 Washington Blvd, Mundelein, IL 60060 (USA). 

Jeanne Moldenhauer

The FDA provides an electronic reading room on its website that provides access to a great deal of useful information, including copies of Warning Letters issued by the FDA. Reviewing these letters can be useful because they provide insight into the inspection techniques and concerns of FDA inspectors. Additionally, they can be used to perform gap analyses of the processes used at your company in preparation for an FDA inspection. This article provides a summary of the review conducted for Warning Letters issued between 2000 and 2010 for products that are aseptically filled and for manufacturing processes identified as non-sterile. 

Employee training in a pharmaceutical company almost always includes instilling a 'healthy fear' of regulatory agency inspections. Most, if not all, countries have established governmental agencies that are responsible for the safety and efficacy of the medicines manufactured, sold and distributed within their country. These agencies typically have the legal authority to go into production facilities to assess various aspects of the manufacturing and distribution facility. As such, employees learn that the company's viability is dependent upon successfully passing these inspections.

The notification that a regulatory inspector is planning a visit to a company site can trigger concern regarding the expected outcome and frantic activities often take place in preparation. Since the implementation of the FDA's Systems Based inspection programme, however, it has become more difficult to successfully prepare for an inspection. 

Originally, the Systems Based Inspection guide was introduced by the FDA as a pilot programme.

  The method for evaluation entailed a portion of the FDA's regional offices using the programme for a 6-month trial period in 2001. The results were successful and the FDA officially implemented the programme in 2002 as the 

Compliance Program Guidance Manual for FDA Staff: Drug Manufacturing Inspections

Prior to the implementation of this guidance, companies prepared for inspections by thoroughly reviewing and assessing products with upcoming pre-approval inspections because these products tended to be the focus of the inspection. Under the new guidance, however, the FDA reviews companies in a systematic approach, which makes it more difficult to prepare. One valuable way to prepare for an inspection is to look at the FDA's inspection findings from other companies to determine which types of observations are also issues at your company.  

For this study, the FDA's website was searched to review the Warning Letters issued between 2000 and mid-2010. The searches were limited to those referencing aseptic processing or non-sterile processing, and the data were summarised.

Data obtained from the Warning Letter review were analysed to determine the appropriate section of the GMPs, as stated in 21 CFR Part 211, that had been violated. This was then summarised to determine how many observations were made for each section of the GMPs. Following determination of the number of observations made, a ranking was performed to determine which section resulted in the most observations (rank = 1) and which resulted in the least (rank = 33 for aseptic; rank = 44 for non-sterile processing). Items with the same number of observations were given the same ranking within the type of processing used. These results are summarised in 

. The top ten categories of observations for each type of processing are summarised in 

Table 1: Number of FDA observations made per section of the Code of Federal Regulations, 21 CFR Part 211.			

Although the product processing types were different (aseptic 

 non-sterile), among the top ten categories of observations, several made the listing for both types of processes; for example: responsibilities of the quality control unit, equipment cleaning and maintenance, written procedures and deviations, general requirements (laboratory controls), testing and release for distribution, batch production and control records, and production record review.  

Table 2: Top ten categories of FDA Warning Letter observations.			

The following sections describe some of the types of observations made by the FDA relative to the cited GMP section. Only sections that ranked in the top five for each process type are covered. 

Design and construction features — Rank number 1 for aseptic

Examples of the types of observations made include: 					

Material flow throughout the building is not designed to prevent contamination.

Lack of separate or defined areas to prevent contamination or mix-ups.

Failure to have an adequate air supply filtered through high efficiency particulate air filters under positive pressure, regardless of whether it is or is not laminar.

Failure to have an adequate system for monitoring environmental conditions or the system established is inadequate. Air sampling is not performed at critical sites. 

Control systems used to prevent contamination do not include floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable.

Failure to establish an adequate system for cleaning and disinfecting the room and equipment.

Studies were not performed to show the adequacy and efficacy of the cleaning and disinfection process used.

Airflow pattern studies were not performed where connections were made.

Inadequate containment control and monitoring programmes.

Appropriate written procedures for prevention of microbiological contamination were not established or followed.

General requirements (laboratory controls) — Rank number 1 for non-sterile manufacturing and number 7 for aseptic processing

Failure to follow scientifically sound and appropriate sampling plans.

Laboratory controls do not include establishment of scientifically sound and appropriate specifications.

Laboratory equipment is not sufficiently calibrated and qualified at suitable intervals, in accordance with an established written programme.

Laboratory controls are deficient. Procedures allow for averaging of out-of-specification (OOS) and within specification analytical test results from separate samples.

New methods do not include sensitivity (limit of quantitation), linearity, accuracy or an appropriate precision method.

Failure to qualify the supplier of the raw material.

Methods used for stability testing are not stability indicating.

Method validation is inadequate. It does not address all variables.

Laboratory controls do not include determination of conformance to written specifications for the acceptance of each lot within a shipment of components used.

Test devices are deficient. They did not meet established specifications and were used.

Failure to ensure that complete data derived from all tests are documented at the time of performance.

Failure to follow your stability programme.

Control of microbiological contamination — Rank number 2 for aseptic processing

Failure to follow procedures designed to prevent microbiological contamination.

Failure to adequately assess and monitor the aseptic environment.

Failure to establish and follow appropriate written procedures.

Articles

The author reviews Warning Letters issued between 2000 and mid-2010 for aseptic processing and non-sterile processing, and determines how many observations were made for each section of the GMPs.

Review of FDA Warning Letters

Editor's Note: This article is part of a special feature on cleanrooms that was published in the December issue of PTE Digital.

A review of warning letters from the last 10 years relating specifically to cleanrooms has indicated several concerns with the appropriateness of cleanroom design — primarily regarding air flow and laminarity. Additional citations have been made about area maintenance, e.g., in need of repair, presence of "rust", peeling or damaged surfaces, and so forth. Meanwhile, additional observations have related to monitoring plan inappropriateness/insufficience and the poor aseptic behaviour observed within the cleanroom. 

To reduce the chance of receiving a warning letter, companies must review the design features of a cleanroom on a regular basis and take appropriate corrective actions to ensure that both airflow and laminarity are maintained, especially when personnel are operating in the area. Maintenance issues could be mitigated by conducting routine and frequent checks of both the condition of the area and the equipment, ensuring that concerns are quickly repaired. Cleanroom monitoring programmes should also be routinely reviewed to determine whether they reflect current, stateofthe art thinking. If not, the programmes should be updated as appropriate. Finally, poor aseptic behaviour must be mitigated with training and retraining of operators. This should be supplemented with supervisory oversight and coaching, as appropriate. 

It is important that a group or person within a company is responsible for keeping abreast of current regulatory trends, e.g., by reviewing recent warning letters, benchmarking against other companies, reviewing literature, and assessing the company's performance against current trends and standards. 

Best practice for environmental monitoring

It is a little more difficult for companies to meet all of the requirements for environmental monitoring. First, one must understand which regulatory requirements are applicable. There are compendial monographs in the USP, JP and EP; guidance in various regulatory documents; GMP requirements for Europe; GMP requirements in the US FDA's Aseptic Guidance; ISO Documents; and World Health Organisation documents, to name a few of the applicable requirements. 

Many traditional companies use programmes that were established more than 10 years ago. While the programme may still evaluate a state of control, it may not appropriately implement the current regulatory expectations.  

In order to define an appropriate environmental monitoring programme, it is advisable that companies use risk assessments to determine the appropriateness of sample locations, monitoring equipment and control levels, as well as in determining the types of organisms that should be considered "objectionable" to the process. Once these parameters have been defined, the process of developing an effective environmental monitoring can begin. 

A review of warning letters from the last 10 years relating specifically to cleanrooms has indicated several concerns with the appropriateness of cleanroom design - primarily regarding air flow and laminarity.