How a simple mistake can leads to a warning letter

Nasir Ansari

Piramal Enterprises Limited

Pithampur

Perspective of GMP & GDP challenges in India

FDA-483 observation trends has been a frequently requested topic for years, but WHAT IS REALLY AN FDA-483 OBSERVATION?

Introduction

IOM (Investigational Operational Manual) 5.2.3 - REPORTS OF OBSERVATIONS The FORM FDA 483 INSPECTIONAL OBSERVATIONS (see Exhibit 5-5) is intended for use in notifying the inspected establishments top management in writing of significant objectionable conditions, relating to products and/or processes, or other violations of the FD&C Act and related Acts (see IOM 5.2.3.2) which were observed during the inspection.

These observations are made when in the Investigator's "judgment", conditions or practices observed, indicate that any food, drug, device, or cosmetic have been adulterated or are being prepared, packed, or held under conditions whereby they may become adulterated or rendered injurious to health.

IOM 5.2.3 - REPORTS OF OBSERVATIONS

483 trends FY 15

483 trends FY 15

Four (4) US drug manufacturers (including one API manufacturer) Thirteen (13) foreign firms Several were issued for inspectional findings at two different sites of the same company Some issued to OTC drug manufacturers, repackager/relabeler, contract lab, etc

2013 CDER Warning Letters

The most observable trends were reported for foreign establishments Data integrity Failure to protect computerized data from unauthorized access, changes, or deletion Failure to review and investigate production and QC laboratory deviations - Lack of training

- Facility and equipment.

- Production system

- Material system - Packing and labelling

2013 CDER Warning Letters

HPLC processing methods (including integration parameters) and re-integrations are executed without a pre-defined, scientifically valid procedure The audit trail function for the chromatographic systems was disabled at the time of the inspection QC laboratory personnel shared the same username and password for the operating systems and analytical software on each workstation in the QC laboratory No computer lock mechanism had been configured to prevent unauthorized access to the operating system Failure to implement access controls and audit trails for laboratory computer systems Use of the Excel spreadsheets in analytical calculations are neither controlled nor protected from modifications or deletion

Data integrity issues

The management of electronic data permitted unauthorized changes, as digital computer folders and files could be easily altered or deleted.

Data integrity issues

When weighing samples, reagents, and other laboratory materials, QC analysts write weight values on small pieces of paper, transcribe the values onto the analytical worksheets, and then destroy the original paper on which the weights are written.

Testing samples unofficially, and not reporting all results obtained. Specifically, test, trial and demo injections of intermediate and final API samples were performed, prior to performing the tests that would be reported as the final QC results.

Out-of-specification or undesirable results were ignored and not investigated Samples were retested without a record of the reason for the retest or an investigation. Only passing results were considered valid, and were used to release batches of APIs intended for US distribution. During the inspection, management acknowledged that the some of the chromatograms observed were related to the practice of blending an API batch that failed to meet specifications with an API batch that passed specifications. The combined batch was retested and distributed using the new acceptable Quality Control results. Failure to record all quality activities at the time they are performed Documenting operations before execution

Data integrity issues

Lack of or inadequate investigations (production, manufacturing and complaints) continue to be one of the most frequently cited observations in FDA-483s and WLs both for foreign and domestic establishments Failure to conduct an investigation into unexplained discrepancies (atypical peaks) observed in the related substance assay results for multiple API batches Failure to investigate the source of foreign particles in an API Failure to investigate OOS results Failure to investigate reports of mold in HEPA filters Failure to properly investigate complaints Scope of CAPA is restricted to specific event . Expected to be global or with wider systemic applicability

Investigations

Why is Industry still having issues with the quality of investigations?

Investigations

Answer will vary on a case by case basis, no one size fits all answer is possible Requires an intimate knowledge and understanding of the specific companys culture Lack of knowledge of the issue being investigated Lack of a multi-disciplinary approach Lack of adequate resources to conduct appropriate investigations

Why is Industry still having issues with the quality of investigations? It is often uncomfortable to find the real root causes. When the 5-Whys is used, the investigation often stops at the point where it becomes uncomfortable or intrusive. Industry comment in a conference

Investigations

Investigations

Why is it uncomfortable to find the real root causes? Addressing root cause may require rejecting or recalling products, or submitting post-marketing reports (NDA Field Alerts, BPDRs) Root cause may indicate that employees are not following procedures Root cause may indicate data integrity issues Root cause may indicate major systemic and or cultural issues, or a QU failure Other reasons???

Consider this example The knife used for slitting transdermal patches widened during operation due to vibrations, so that four slit rolls were cut wide. The rolls were rejected. The operator repeatedly documented the wrong measurement on the batch record, during five in-process checks. The difference between actual and documented was 0.5". The actual knife width was not found until the next shift's operations. The interview in the investigation stated that the operator might have misread the measurement.

Investigations

Investigators background and expertise Regulatory maturity (regulators and inspected firms) Inspection logistics FDA foreign posts Geographical location of inspected firms Availability of required expertise Company culture Management oversight Resources Others

Inspectional Findings and Trends - Some Contributing Factors

Lack of training

Lack of cGMP knowledge. Employee not trained on their specific job functions prior to

performing. No formal system identify and track needs for each employee. Refresher GMP not conducted with sufficient frequency. Personnel not trained when process are revised. No competency/ skill matrix for technical duties. Trainers not qualified for training. Employee not proficient in language of SOPs.

Since 2010 approx. 66 compliance action.

Facility and equipment

Surfaces and finishes, ducting and pipes not proper. Toilet flush not working properly. Water leakages and microbial growth in cold rooms. Rusting on light fixtures. Entry Exit door does not have a mechanism to slow during closure.

Production system

Automatic login and manual entries for process control. Reporting of deviations/incidences. Log not maintained. Calibration frequency not maintained. Not recording all steps involved in the processing.

Packing and labelling.

Validation of packing line is inefficient. Missing/error labels. Improper line clearance. No tracking system to trace back in case of complaint. No specimen or approved copy in master production record.

Material system

Old and rejected lots were found. Failure to describe about FIFO failure. No proper storage condition. Vendor qualification. Wooden pallets

The Trends In GMP Compliance 2012 indicate there is a problem with GMP thinking in the global pharmaceutical sector.

The regulators know this , customers/consumers know this.

Manufacturers know that, it is going to become more difficult and more expensive to be in this business.

India is no exception

GMP challenges in India :Introduction

Increasing Number of Inspections

Increasing Number of Warning Letters.

Current Regulatory Environment

more than 350

warning letters have

been served to

companies in different

parts of the world so

far this year

In 2012 , FDA

conducted 40,000+

inspections Globally

241 inspections in India

Increasing Harmonization between Regulatory Agencies

Increasing Use of Science and Technology

Increasing Use of Subject Matter Experts

Increasing Enforcement Penalties

Product vs. Process

Most Warning Letters, including most of those that focus on GMP issues, are not reactions to product failures. Rather, the bulk of the warnings reflect instead the FDA's increasing focus on the processes and procedures that are intended to prevent defects.

For manufacturers, this means that there is no substitute for

thoroughness and diligence, and that the process of manufacturing is as important as the results.

Is Indian scenario different?

Listing out the problems encountered by its investigators in India, a senior FDA official said these were similar to those seen around the world and include issues associated with-

Quality systems implementation,

Data integrity,

Validation of various processes used in manufacturing or testing

GXP challenges

Best of systems may fail

The challenge is, do we know?

- how did it fail ?

- how did we know that it had failed ?

- what to do when it fails and who does what ?

- what do we learn and do that it does not fail again ?

- how do we assess the risk of failure

Components of GXP challenge

Challenges from Product

Scale up and manufacturability issues

Storage and processing condition issue

Robustness and stability issue

Testing and analytical issues

Packaging issue

Challenges from People

Quality ownership

Reporting ( Deviation) on line ,Raising Flag

Disconnect between documented process and operating reality

(Referred commonly as human error)

Challenges from People- Human error

Analysis of investigation reports reveal that human error is one of

the top root causes for deviations, discrepancies and quality

incidents in pharmaceutical manufacturing.

When one examines the CAPA's that are developed from these,

retraining and rewrite of SOP ,top the list.

Yet on further re-examination, one would find that these

problems keep resurfacing again and again. Put in another way, the

CAPA's are ineffective

Challenges from people

Humans do contribute to problems but more often than not "human

error" is not really the problem but a symptom of a system or facility

or operation that is not designed to be run by humans, realistically.

So a true CAPA focus on the Error Risk Reduction (ERR) process and identifies the Risk Induction factors (RIFs) and reduces their effects, rather than remediation of people.This requires investigations to focus on getting to the real root cause and contributing factors.

Challenges from Process

Batch reproducibility and Process validation.

Clear understanding of the processes in order to define the design and control parameters that determine the limits and operating sphere

Maintaining Validated state over Product and process life cycle for both new, and legacy products

Challenges from Process

Cleaning validation vs. dedicated contact part/ equipment

Availability and application of appropriate measurement technique

Reliability of People dependent process

e.g. Aseptic techniques and operational practices, Visual

inspection, Sampling, Manual data recording, Document

Review , Manual end point detection, etc.

Optimizing Pharmaceutical Asset-Life-cycle management

Pharmaceutical facilities are critical assets. They reflect the final investment phase in the development of pharmaceutical products that take many years and hundreds of millions of dollars to bring to market. Typical concerns

-Supply interruption - Regulatory impact - Product quality Impact - Time ( opportunity loss)

- Cost ( revenue loss)

Pharmaceutical asset life cycle

optimization

Examples of failure causing long facility stoppage

Failure of Purified water system/ water for Injection system

Failure of steam generation system

Failure of chiller/ refrigeration system

Failure of Sterilizing tunnel / Autoclave

Failure of Air handling unit for aseptic area

Failure of Granulator/ Reactors

Pharmaceutical Asset

Top 6 challenges for life cycle management

Asset condition and operational visibility

Making changes without enough reliable data Finding ways to extend the life of existing assets Obsolescence /non availability of spares /components

Vendor management to get right quality of service

Redundancy management

Capacity Planning as Risk mitigation tool

Considering a capacity planning, covering the whole enterprise, and extended enterprise at least 5 years down the line is rare . A capacity planning from Risk mitigation point of view should cover (other than conventional receiving , storage , dispensing, processing ,testing , packing , distribution and logistics area) the following Process complexity, Process and method transfer & validation, Stability program management, Document management , Retained sample handling, Complaint handling, Event / incidence investigation, Document review, Facility- equipment- instrument maintenance& calibration .

Every single medicinal product in transit, in any part of the world, is potentially at risk of theft, falsification , breakage, damage, breach of integrity, abnormal excursion of storage condition

Supply chain challenges will vary depending on the geographical region of origin and destination of medicinal products, coupled with climatic and weather condition dimension Common challenge areas are

-Practices in Storage and Transportation -Cold Chain and its Validation -Security in the Supply Chain -Quality Risk Management - Tracking and Tracing

Supply chain Challenges

Supply chain challenges

Globalization, counterfeiting problems and the expectations regarding pharmaceutical storage, transport and cold chain management are forcing the pharmaceutical industry to challenge their current practices.

Companies have to increase their effort and validation activities as one prerequisite for safe and secure storage and transportation of their medicinal products over and through various climatic conditions