Paula R. Katz, acting branch chief for Regulatory Policy and Collaboration, US FDA, CDER/Office of Compliance/Office of Manufacturing and Product Quality.

Paula R. Katz

The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) plays an important role in bringing regulators from around the world together to develop better ways of exchanging information, reach and maintain mutual confidence and uniformity, share inspectional plans and findings, and provide specialized and advanced GMP/technical training. This article focuses on PIC/S’s efforts to train inspectors from around the world on APIs and describes some of the most common deficiencies found by PIC/S members (inspectorates) during inspections of API manufacturing facilities.

PIC/S, through its different working groups, expert circles, and training forums, has evolved as an organization making a significant contribution in training inspectors in GMPs by maintaining the highest level of technical competency of inspectorates. While the 43 member authorities of PIC/S are responsible for having their own local training, PIC/S facilitates international technical training on relevant topics of interest. One of the most active bodies within PIC/S is the API Expert Circle. Its efforts and strategic plan are focused in four key areas: identifying regions and countries where the inspectorate and industry have greater needs of GMP training in APIs; providing the inspectorate with up-to-date information on advanced or complex APIs manufacturing processes; through partnership with technical organizations and established procedures, ensuring that the inspectorate is exposed to new technology while industry receives relevant information regarding current inspectional findings and regulators, expectations in the area of APIs and; offering discussion and training on emerging regulatory issues for APIs. Thus far, five API Expert Circles have been held, the most recent in September 2012, in Washington DC, where approximately 130 inspectors were trained on sterile APIs and biotechnology manufacturing. The 6th Expert Circle on APIs will be held in Rome on May 19-21, 2014 on the topic of API process validation and contemporary issues. While these Expert Circles, designed only for inspectors, are organized, other efforts are ongoing. PIC/S and the Parenteral Drug Association (PDA) have developed a training course for industry and regulators on International Conference on Harmonization (ICH) Q7, 

Good Manufacturing Practices for Active Pharmaceutical Ingredients 

(1). The next course is scheduled to take place in Johannesburg during March 18-19, 2014 (similar training has been held in Lisbon, Portugal, and China). Other training and seminars are being planned with PDA and other organizations to allow for diversity.


   Since the implementation of Q7, most API manufacturers appear to have a better understanding of GMP principles.  Many firms have good quality systems, process understanding, seek opportunities for optimization, have robust change-controls systems, and have good laboratory controls and procedures to facilitate knowledge management. On the other hand, inspections also reveal that some API manufacturers continue to struggle with achieving sustainable compliance with GMP requirements.  

Inspections of API facilities, conducted by PIC/S members, have recently been reporting critical deficiencies related to laboratory controls, records/investigations, quality systems, equipment cleaning/maintenance, and process validation. 
   The top GMP deficiencies cited by FDA in 2012 were:

 Lack of/inadequate method validation; failure to have scientifically sound and appropriate specifications and test procedures; failure to adequately investigate out-of-specification results; failure to document activities at the time of performance; and failure to have adequate stability testing programs to assess the quality attributes of the API throughout its expiry date.  

 Failure of the quality unit to release/reject APIs; failure of the quality unit to review and approve all quality-related documents; failure to ensure that quality-related complaints are investigated; failure to conduct regular quality reviews of the APIs; and failure to evaluate the impact of changes in the quality of the APIs. 

Equipment, cleaning, maintenance, and validation. 

Equipment not being properly maintained; deficient cleaning procedures; failure to validate cleaning procedures; failure to clean, store, or sanitize equipment to prevent contamination or carryover that may alter the quality of APIs; and inadequate qualification of critical equipment.  

 Failure to prepare adequate batch records; failure to include complete data of all test performed; failure to establish written procedures related to production, quality, laboratory controls, and material management.   

During 2011, 12 of 20 Warning Letters issued by FDA were issued to API manufacturers; while in 2012, 7 of 23 Warning Letters were issued to API sites. One of the seven was to a site that produced both API and finished product. As of August 2013, 6 of the 26 Warning Letters were issued to API manufacturers.

Similar findings have also been found by other PIC/S members as well as by European Directorate for the Quality of Medicines & HealthCare (EDQM), which is a partner of PIC/S. In 2012, EDQM performed 32 inspections of API manufacturers located mainly in Asia, of which 13 showed serious GMP noncompliance findings or noncompliance to the Certificate of Suitability to the monographs of the 


PIC/S members and partners have also noted an increase in findings of data-integrity practices during inspections of API sites. These deficiencies include: recording data in logbooks, falsification of batch records and test results, pretesting samples and ignoring or not investigating out-of-specification results, blending or mixing API batches that failed to meet the established released specifications with batches that met the required final specifications, lacking the necessary controls in handling and managing critical data, and entering manufacturing activities on records before they had occurred.

Although the principles set forth in Q7 won’t correct the behavior of firms that intentionally engage in deceptive or wrongful behavior, companies that seek only to comply with the bare minimum principle, rather than pursuing a robust and sustainable quality framework, will always find themselves operating in a reactive mode and are more likely to tangle with challenging data-integrity issues. 

Outsourced operations and the changing face of API manufacturing


  With the increase in the outsourcing of APIs by sponsors/drug applicants/finished drug product owners/contract givers (party that purchases APIs), there is more concern about how the roles and responsibilities of each party are established and managed. The following are some questions regulators ask during inspections:

How does the owner of the marketing authorization (drug application in the US) assure that the API manufacturing facility is operating in a sustainable state of control?

What quality framework or policy does the API manufacturing site have in place?  

Does the quality agreement describe each party’s responsibility? 

Who is responsible for overseeing compliance with the quality agreement?

How are quality issues communicated and handled?

Are the quality issues identified isolated or do they reflect a broader pattern?

What metrics are used to monitor process performance and product quality?

How are quality attributes measured, trended, communicated, and used to make product and process improvements?

Is senior management committed to quality? How is senior management engaged in understanding, resolving, communicating, and providing resources to quality issues?

Is the manufacturing process well designed and clearly understood by operators and quality/production personnel?  

How are critical changes implemented: as a result of innovation, through continual improvement processes, in response to poor process performance, or in response to corrective action and preventive action (CAPA)? 

Is there a strong scientific and regulatory understanding of the process to assure that the appropriate CAPA has or will be implemented when needed?

  
  A regulator’s role is to determine whether firms are operating in sustainable compliance with GMP for APIs, pursuant to ICH Q7. In connection therewith, PIC/S has also recently reviewed hundreds of Q&As related to ICH Q7 and transferred its review to ICH for consideration. During PIC/S’ API Expert Circles, inspectors are trained on new technology, quality trends, and critical deficiencies and how to detect problems that may affect the quality of the APIs produced and that may impact the finished drug products, and subsequently affect the patients who consume these medicines. Bearing in mind that inspections are limited by time and other resource constraints, regulators rely heavily on manufacturers to implement and maintain appropriate quality systems and processes to ensure that all APIs produced meets the required quality standards. As new challenges are faced regarding the supply and availability of APIs and pharmaceutical drugs in general, regulators need to move away from the model of being the problem finders for industry. Instead, firms should be expected to proactively design and implement quality systems that drive API-manufacturing facilities to operate in a sustainable state of control. When API manufacturers operate under fragmented quality systems, disconnected quality management structures, or lack management commitment to a strong quality culture, data integrity problems may be more prevalent and may impact the quality of the APIs produced. 

Good Manufacturing Practices for Active Pharmaceutical Ingredients

Articles

PIC/S reviews deficiencies found during inspections of API manufacturing facilities, harmonizes GMP standards, and provides training for inspectors worldwide.