Analysis on the issues raised by the regulatory authorities on Indian Pharma companies and inputs provided by them

D Naveen Kumar
Senior Manager
CARE Ratings Ltd

Vidhyasagar L
Associate Director
CARE Ratings Ltd

Pharmaceutical industry across the globe bench marks the standard of regulatory processes carried out by Food and Drug Administration of USA (USFDA). India which has th e highest number of USFDA approved plants outside of USA itself, has been confronted with slew of warning letters and import alerts from the said regulatory authority, which especially were accentuated during last six years i.e. from FY13-FY18. The current article delineates upon analysis on classification of violations cited by FDA for Indian Pharma cos, inputs provided by them while concluding with solutions to overcome majority of the regulatory observations.

With market size of around $ 35 bn in FY2018, Indian pharmaceutical industry is ranked third globally in terms of volume and thirteenth in terms of value . Indian pharmaceutical companies, over decades of arduous efforts, have gradually developed the necessary technology, capacities and capabilities to meet the demand and to explore the opportunities provided by global regulated markets; and currently, United States of America (USA) contributes about one third of the total Indian pharmaceutical exports. Furthermore, Indian pharmaceutical manufacturing companies accounted for 36% of the total Abbreviated New Drug Application (ANDA) approvals by USA in 2017 as compared with 34% in 2016; the total number of ANDA approvals has increased from 201 to 304 during the same period. India has second highest number of USFDA (United States Food and Drug Administration) approved manufacturing plants, ie, about 700 units with over 5000 ANDA approved drug products during last decade i.e. 2008-2017.

With all the aforesaid accolades, however, lately, it has been noted that there has been a spurt in the issuance of the import alerts and warning letters for domestic manufacturing facilities significantly over the past years following USFDA's increasing focus on compliance of guidelines of cGMP . This restricts the manufacturing units to supply drugs to the US market from that facility resulting in the decline of revenue for the companies particularly to US market and also from other markets subsequently if the issues are not closed out to the earliest.

Sequence observed by USFDA in regulatory enforcement:
USFDA's Offi ce of Regulatory Affairs (ORA) is the lead offi ce for all the field activities, including inspections and enforcement, which carries out the inspections of the manufacturing facilities approved by them in regular intervals. At the completion of inspection a report is prepared by the agency and is termed as 'Establishment Inspection Report' which details inspectional findings.

All the inspections carried out USFDA are categorized in three buckets: No Action Indicated (NAI), Voluntary Action Indicated(VAI) and Offi cial Action Indicated (OAI).

NAI = No Action Indicated, meaning no objectionable conditions or practices were found during the inspection (or the signifi cance of the documented objectionable conditions found does not justify further action).

VAI = Voluntary Action Indicated, meaning objectionable conditions were found and documented but the agency is not prepared to take or recommend regulatory action.

OAI = Official Action Indicated, meaning objectionable conditions were found and regulatory action should be recommended.

Out of the total inspections carried out during CY12 and CY13 about 33% of cases were categorized under Offi cial action indicated and the same during CY15 and CY16 in this category were 29% and 20% respectively, which subsequently were converted into warning letters and alerts. However, during CY17 the total number of cases falling under OAI has reduced to about 14%. India having experienced the headwinds from the heightening regulatory requirements during CY12-CY16, have improved their processes leading to lower inspections falling under OAI category during CY17.

A warning letter restricts the ability of that manufacturing unit to supply new drugs to the US from that facility. The company in that case needs to appoint consultants to advice on corrective actions and also monitor implementation of the same. After this, the company approaches the FDA and makes a request for re-inspection. If the regulator is satisfied with the corrective measures, it can issue a close-out letter.

However FDA can also choose to issue Import Alerts immediately whenever it determines that it already has sufficient evidence to conclude that the products manufactured from a specific unit appear to be adulterated, misbranded, or unapproved, and has made serious deviations from cGMP, then they may be refused from importing. In such cases warning letter would follow the issue of import alerts. The basic purpose of import alert is to prevent voilative products from being circulated in United States; provide uniform coverage across country; and place the responsibility back on the importer to ensure that the products being imported into the United States are in compliance with FDA laws and regulations.

Post to issue of import alert the company needs to implement appropriate remediations process religiously. Once the company is confident about its processes, it can invite USFDA to carry out the inspection post to implementation. Once the FDA finds that all the process are in place then unit can restart the export of the drugs to US.

Note: The import alert falling under the category 'Detention Without Physical Examination' (DWPE) 66-40 pertains to the Drugs from firms which have not met Drug GMPs.

The following table and graph delineates upon the entire classifi cation of observations mentioned in warning letters received from USFDA into various categories and it can be inferred that that about 50% of the warning letters issued to the Indian Pharma companies pertain to Data manipulation, data integrity and lack of data documentation discipline.

Followingare some of the inputs provided by the regulatory authorizes and consultancies in order to avoid the observations and incorporate systems in place:
  • To maintain strong systems in place with proper qualified and designated personal to handle the data in order to prevent unauthorized access or changes to data, and to provide adequate controls to prevent omission of data.
  • As about 50% of the observations pertain to data integrity, manipulation and/or discipline, USFDA necessitates that a pharmaceutical manufacturing company approved by it to observe standard operating procedures meticulously. Further those SOPs have to clearly written, modified, and maintained in a consistent and timely manner, and be centrally accessible. Problems and accidents generally take place if the employees do not have current written instructions for their tasks or if they do not observe written instructions in toto.
  • To maintain complete data derived from all testing, and to ensure compliance with established specifi cations and standards as many data integrity observations fall under the category "Failure to provide records required to be readily available for authorized inspection".
  • To maintain the buildings used in the manufacturing, processing of a drug product in a clean and sanitary condition and keep them free of infestation by rodents, birds, insects, and other vermin.
  • While addressing the observations made by the regulatory authority, the company needs to take care that every observation should have a thorough root cause analysis performed and, if necessary present, one or more corrective and preventive actions identified very clearly with specific timelines of implementation.
  • It is in the benefit of the company to peruse to obtain closeout letter at the earliest for which the remediation process should start right from the day of receipt of Form 483 or a warning letter. USFDA generally looks for a response to most of its compliance notices within 15 business days. The USFDA, although doesn't confirm to the company's response immediately but it would be appropriate to contact the agency and confirm receipt.
As majority (about 50%) of the observations fall under data integrity, manipulations and discipline category the best approach for minimizing the human errors is to establish a system where each step has to be followed by implementing an enterprise quality management software system. The plausible and best-practice features include prompting users with selected data which is just need to be accessed or entered by the specific task performer. This would signifi cantly reduce data entry related errors and avoid mistakes common in manual document management and data entry. Apart from above the implementation of aforementioned systems would also take care the procedural errors.