Siegfried Schmitt, PhD, is Vice President Technical at Parexel International, Siegfried.Schmitt@parexel.com.

Siegfried Schmitt

Data integrity has been making headlines recently, in response to foreign inspections by FDA and European regulatory agencies (1). Based on these reports, it appears that data integrity issues center largely on manufacturing companies in Asia. Should we conclude that these issues only concern firms already struggling to comply with basic good practices in this part of the world?

 In general, media tend to report on the most serious violations uncovered by regulators. Often when companies find similar issues through their own internal investigations, they remain confidential and unreported. It would, therefore, be presumptuous to assume violations reported on by the press are representative of the industry as a whole.

What inspections have triggered, however, is increased attention toward potential data integrity issues lurking across the industry. Few companies would have data integrity verification activities integrated into their quality oversight programs before these examples of serious violations of healthcare regulations became public knowledge in the form of warning letters (2), consent decrees (3), or reports in the European EudraGMDP database (4).

Conscientious companies have taken these potential data integrity issues seriously by starting internal investigations, incorporating data integrity assessments into their quality assurance oversight programs, and in some cases, establishing a special data integrity office. Companies—even those in good standing with regulators--have initiated such activities regardless of existing or anticipated compliance concerns.

The question is: what have these internal investigations uncovered, if anything? The answer, surprisingly, is that they have uncovered a significant amount. Once you start studying analytical data, root cause analyses, logbooks, and any other data source, gaps are repeatedly found in data traceability and trustworthiness. A few data-related issues include: uncertainty where the data originated from and who created it (e.g., where several analysts use the same user ID and password on a set of similar instruments); which raw information produced the reported data (e.g., where a summary table reports stability data results, but all raw data on the chromatography instrument have since been deleted); and whether these are the original data (e.g., where there is no audit trail on the analytical instrument). These issues are not necessarily the result of willful malpractice, but are often caused by insufficiently controlled processes, poor documentation practices, suboptimal quality oversight, and often enough, professional ignorance.

Occasionally people do intentionally falsify data. This is unfortunate but, thankfully, still a rarity. 

The following are some steps companies should take to ensure data integrity:

Embed data integrity verification activities into internal audit processes

Create awareness among staff so they can assist with this endeavor, and report concerns before they become full-fledged issues

Train internal auditors to understand what to look for when detecting data integrity deficiencies

Seek external support to assure completely unbiased, third-party investigations and/or to enhance your internal investigation program.

It should come as no surprise that companies already struggling to meet basic compliance standards are at a disadvantage when it comes to data integrity. Making data integrity a key element of a compliance approach, however, will give the company a competitive advantage. It is always better to proactively prevent issues, such as data integrity failures, to occur, than trying to remediate and resolve inspection findings. Compliance excellence makes good business sense. 
  

MHRA expectation regarding self inspection and data integrity

Warning Letter to Sun Pharmaceutical Industries Limited

Department of Justice files consent decree of permanent injunction against Ranbaxy

, Press Release (Jan. 25, 2012).
4.	EMA, 

 Siegfried Schmitt, Principal Consultant, PAREXEL International.

Articles

Siegfried Schmitt, Principal Consultant, PAREXEL International, discusses how to ensure data integrity.

Data Integrity

We are part of a multinational company, and some regulated activities, such as supplier audits, are pooled at the corporate head office. In a recent internal audit, we received a finding that there were no quality agreements in place between the site and the head office covering these activities. Surely, as we are one company, no such agreements are needed?

‘If it is not documented, there is no proof of evidence.’ While the company may be following an old adage, internal auditors were correct in documenting this deviation from good practices. Close collaboration and a common understanding of work practices among staff does not absolve anyone from having documented processes, roles and responsibilities, and defined documentation requirements—all commonly referred to as a quality-technical agreement. 

The basis for this can be found in relevant regulations by the European Medicines Agency (EMA), FDA, the World Health Organization (WHO), Pharmaceutical Inspection Convention/Pharmaceutical Inspection Cooperation Scheme (PIC/S), and the International Conference on Harmonization (ICH) (1-5).

When looking for applicable regulations relating to quality-technical agreements, it is important to note that explicit references to such agreements do not always exist. It is, therefore, necessary to look for other terms, such as contract manufacture or outsourced activities.

Apart from being a regulatory requirement, these mandates make good business sense. Their aim is to reduce errors, timelines, and cost. They should clearly describe all elements of respective roles and responsibilities, inputs and outputs, and expectations from both sides. 

Items to address in a quality-technical agreement include all aspects that affect the identity, quality, safety, potency, and purity of a product, and/or aspects that may affect compliance status of either the contract giver or contract acceptor (6). In a specific case in which suppliers are audited by a corporate function, the quality-technical agreement should clarify, as a minimum

Scope—all suppliers for equipment, raw materials, packaging materials, analyses, services, information technology

Roles and responsibilities—will there be a site review of the report required? What qualifications will be required of auditors?

Deliverables—audit plan, reports, timelines for issuing a report

Communication—regarding dispute resolution with the audited entity

Documentation—Is there a standard template for audits?

Finally, consider tracking agreement effectiveness through well-defined metrics. For every particular case, these metrics could include on-time delivery and in full (target 95%) and the number of audits overdue per quarter (target no more than 1; none for critical suppliers).

Just because activities are being outsourced, even if only to other entities within a company, this does not relieve a company of responsibility. On the contrary, a biopharmaceutical company must continue to assume responsibility, and quality-technical agreements are an important way to help ensure and retain this control.

Guidance for Industry, Contract Manufacturing Arrangements for Drugs: Quality Agreements, Draft Guidance

Pharmaceutical Production and Related Technology Transfer

, 2011, accessed Apr. 11, 2014. 
  4.	PIC/S, 

Technology and Knowledge Transfer, Keys to successful implementation and management


Siegfried Schmitt, Principal Consultant, PAREXEL International, discusses the importance of quality-technical agreements. 

A drug sponsor?s responsibility does not end when a task is outsourced.

Key Considerations for Quality-Technical Agreements

Siegfried Schmitt, principal consultant at PAREXEL, discusses the importance of quality-technical agreements.

Quality-Technical Agreements

 Regulatory inspections often list operator errors or other mistakes performed by personnel as either violations of the law or issues that could lead to non-compliance with relevant healthcare regulations (1). These observations might read as follows: “Out of specification (OOS) results were attributed to human error in sample handling and preparation for testing,” or “…you did not discuss measures to ensure that your standard operating procedures (SOPs) are adequate or explain which steps you are taking to reduce human error in your facility.” The same observations may go on to state: “This failure was due to human error and your firm will retrain appropriate staff on this aspect of the procedure.” 

Because the vast majority of pharmaceutical operations require human input or interfaces, they are inevitably prone to error. What is fascinating, however, is the widespread lack of safeguards and controls that can detect human error with high probability or eliminate them altogether. All too often companies merely retrain their staff in the very SOP they failed to follow in the first place.

Rarely, if ever, is consideration given to these basic questions:

Why did the person not follow the instructions?

Why would a repeat of training be more effective than the original training?

Organizations should consider incorporating similar questions for employees to answer as part of a mandatory exercise for determining the root cause of any human error. This analysis should help reveal the following:

The person was not willing/did not consider it important to follow the procedure

The person did not understand the instructions

The procedure was incorrect, insufficiently detailed, or incomprehensible and could not be followed

The SOP did not describe the actual procedure

The operator was told by management to ignore the SOP

The training was insufficient or incomplete.

It is also possible that the person simply made a mistake and that none of the above scenarios apply. 

  Simple mistake or not, by mandating the above evaluation, the organization will have a complete analysis and record of why its employer made the error. For example: “The right person(s) performed the correct procedure and followed appropriate and relevant instructions, having taken part in the right training program.” Oftentimes, SOPs may contain language that is neither clear nor comprehensible. In some cases, the organization may also find that staff failed to inform management of the need to change or update instructions. Regardless, it is the organization’s responsibility to sufficiently ascertain training effectiveness and encourage continued adherence to instructions.

This is by no means a new viewpoint. In December 1996, FDA described an approach for reducing the likelihood of human error (2). Though additional root causes may be likely, human error is a reality and should be taken into account when designing processes. Eliminating that error requires either removing the human element altogether or, more realistically, developing and implementing adequate safeguards that prevent, minimize, or eliminate negative impact from these errors. The credo should be prevention rather than correction.

D. Sawyer, Do It By Design--An Introduction to Human Factors in Medical Devices

Siegfried Schmitt, Principal Consultant, PAREXEL International, discusses how human error can be mitigated in pharmaceutical manufacturing.

The Human Factor

Some recent high-profile cases of quality issues at Indian manufacturers have given reason to examine manufacturers more closely. What are some issues that should be considered?
  
  

Indian manufacturers of APIs and drug products have been in the news for some time now, mostly under negative headlines. This fact may lead some to believe that there is something fundamentally wrong with them. Before jumping to conclusions, however, we must look closer at the issues at hand.


  Continued cost pressures and increased outsourcing in recent decades resulted in many European and US companies sourcing their APIs from countries, such as India and China, which have lower labor costs. India was an obvious choice for its large pool of skilled and unskilled labor, plus an existing chemical and pharmaceutical industry. Currently, between 50-70% of APIs imported in the US and Europe are sourced from India (1). This is why European and US regulators have conducted many inspections in India, and why FDA even established permanent offices in Mumbai and New Delhi (2). This high volume of inspections has resulted in a large number of findings. 
  
  


  Profit margins for drug products are significantly higher than those for APIs, and several Indian companies have decided to capture their share of this lucrative market, particularly US and EU markets. Regulatory requirements for drug products, especially sterile ones, are much more demanding than those for APIs, and this is where many Indian drug manufacturers face their most serious problems. Warning letters and import alerts have been issued to several leading Indian pharma companies, triggering much of the negative publicity previously noted (3). It is important to note that EU inspection reports are only made public if requested under Freedom of Information legislation from the National Competent Authority, which conducts the inspection. 
  


  Although inspection findings in India reflect those cited elsewhere, what sets them apart is that often data-integrity issues are being singled out in an inspection (4). Therefore, one might conclude that data falsification is rife. Though there is no denying that data-handling irregularities have been detected, there has not always been a malicious intention behind them. In several cases, there has been a misguided belief that data should look good. However, such data manipulation or data invention still constitutes fraud, irrespective of a person’s intention. 
  
Ultimately, Indian drug manufacturers are in the spotlight because of non-compliance issues, such as insufficient environmental monitoring or a lack of documented evidence. Many US- and EU-based companies, however, often times garner attention for the same reasons. This fact is of real concern: why does the mature pharmaceutical industry in Europe and the US still struggle to comply with applicable regulations? If anything, the expectation is that there should be a much higher level of compliance among US and EU companies compared with their Indian counterparts.

Clearly, these issues must be resolved by all Indian companies concerned, just as everywhere else. As remediation efforts are under way, we hope to soon see more positive headlines coming from that part of the world. 

www.specchemonline.com/articles/view/the-falsified-medicines-directive

, accessed Nov. 6, 2013.
  2.	A. Lal,  “FDA In India: Going Global, Coming Home,”

 http://blogs.fda.gov/fdavoice/index.php/2013/09/fda-in-india-going-global-coming-home/

 accessed Nov. 6, 2013.
  3.	FDA, Import Alerts, 

www.fda.gov/forindustry/importprogram/importalerts/default.htm

, accessed Nov. 6, 2013.
4.	“MHRA Cites Wockhardt Plant for GMP Noncompliance, 

www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=825817&topic=368

Some recent high-profile cases of quality issues at Indian manufacturers have given reason to examine manufacturers more closely.

The State of Drug Manufacturing in India

Siegfried Schmitt, principal consultant at PAREXEL, discusses the state of drug manufacturing in India.