5-stages: life-cycle approach on writing an effective technical investigations in pharmaceuticals

PREAMBLE: 

Ineffective investigations have been a key area of focus since decades from the regulatory’s standpoint as well as an equally growing area of concerns for the pharma space at large. Review of overall statistics of USFDA 483’s issued during the year 2013 through 2019 indicates that deficiency related to inadequate investigations (ref: CFR 211.192) have been found as one of the top-most areas of concern with total number of 1553 outstanding observations.

Further an evaluation on the similar deficiencies issued related to “Inadequate Investigations” vis-à-vis total number of “Warning Letters” issued in the years through 2013 to 2018 also indicates that, inadequate investigation is one of the significant areas of concerns for pharmaceutical industry at large, which alone contributes ~ 20% of total WLs issued to pharmaceutical industry and hence a noteworthy arena of improvement in Pharmaceutical industries.

INVESTIGATION PRE-REQUISITES:

A good investigator is a competent person who understand the entire process thoroughly supported by CFTs-SME, while the process involves a set of management skills in art to collaborate the general requirements, the process demands a set of technical skills to conclude the investigation in more a logical way, let us first understand the general pre-requisite vis-à-vis technical /system requirement of an effective Investigation process is outlined below:

GENERAL – PREREQUISITE:

• Understand the purpose of the Investigation?
• Determine the content and flow of investigation process
• Important to have excellent Product /Process knowledge
• Inputs and Output details of variables and impact
• Expert in the field, ask others, meet CFTs, share learning -Coordinator to collaborate
• Should preparing the report in keeping audience in mind?
• Who will read the document? Skilled? Knowledgeable?
• How will the document be used? How often?
• What problems will be encountered? It’s repercussions and risk associated with?

TECHNICAL ATTRIBUTES – REQUIREMENTS:

• Background Introduction
• State the problem
• Specifications vs. results obtained
• Ref SOP & Formats
• Personnel
• Similar Historical events
• Other possible impacted batches
• Immediate corrections
• RCA- Tools used based on type of events/incidents/investigations
• Experiment / investigation and references
• RCA, casual factors and/or Potential causes
• Conclusions, connecting the dots….
• Corrective actions
• Preventive Actions or justification in an event of non-applicability
• Impact/risk analysis and Potential Impact
• Effectiveness Check

STEP-1: INITIATION (GATHERING INFORMATION /DATA): 

Initiation of an investigation process is the first step to begin with right –pathway, while this defined the scope of an investigation process, it also provides clarity about the following;

• Accurate and clear problem statement
• Specific information about event, what, when, where, by whom?

FOR EXAMPLE: -

Correct Problem statement: Dated DD/MM/YYYY, at 23:30 Hours, Laboratory chemist, Mr. XXX noticed an OOS test results as 0.63% in single maximum unknown impurity (RRT 0.34) against the limit of NMT 0.50% in product-X, batch #-XYZ001 etc.

Incorrect problem statement: Higher level of impurity was reported in Batch number XYZ001.

Above example provides a crispy writing with the chronology of event occurred. Further, the problem statement provides the information in specific with accuracy and traceability so that even a reader unfamiliar with technical operation also can understand the fact quickly by reading the problem statement itself. Additionally, adding the specific information such as specific RRT provides explicit clarity to reader, while the OOS is in single maximum unknown impurity as per spec limit but very specific to RRT (could be process profiling or non-process profiling etc.) 

Note: Problem statement specify what has occurred and not why or how and it is part of later stage of investigation process but the common mistakes in problem statement noticed are based on pre-conceived assumptions or past experience , which may be perception but not the fact at the early stage.

STEP-2: PLANNING: (DEFINING- ROAD MAP)

This is a key step and success of an effective investigation process depends on how effectively we can define the road map of an investigation process, the basic steps followed here are 6-W approach depicted below:

WHO: -

• Investigation lead or owner to coordinate with the CFTs using life cycle approach with explicit responsibility
• List of the investigation team members supporting the investigation process.

WHAT: -

• List out what specific items, resources are needed, this may include CFTs, SMEs, specific equipment, instruments, etc.
• For example, this may include the exhaustive list of data, for example, method validation data, forced degradation data, method verification or transfer or to plan further negative experiments etc.

WHEN: -

• Immediately after the data gathering, Gemba-walk is most appropriate way to do before evidences gets disappeared

WHERE: -

• Review room, specific instruments, places of reagents/solutions, analysis -visit shop floor where event was occurred

WHICH: -

• Methodology review, tools to be used in the investigation process, this may include data analysis using 7 Magnificent Quality tools.
• Note: Refer the application of various RCA -tools depicted in technical Article on “RCA-INVESTIGATION-TOOLS” -It’s Application & Benefit to Pharmaceutical Industry, published in Cutting edge, Sep 2017.

WHY: -

• Methodology review, tools to be used in the investigation process, this may include data analysis using 7 Magnificent Quality tools.

STEP-3: EXECUTING (WRITING): -

Objective of an effective investigation report is to express in formal way;

• What do you want to say?
• How do you say it?

The reviewer also understands the same-line you have expressed , while in contrary , few times a huge disconnect is apparent to be in the context it should have been written Vs. the meaning , and in few case a results of geographical- dialect limitation in translation or writings to express on document rightly.

Technical writing is more than just writing, it is the ability of author not just to communicate explicitly and accurately but to maintain the principles of “KISS (keep it short & simple”) throughout the documentations, which itself should be self-convincing to any reader /reviewer even to those are “unfamiliar to subject or operation”. 

The most important elements of the technical writing style are conciseness and clarity, while this provides a sense of confidence in the users in demonstrating the good documentation practices the firm has, sound technical writing go beyond to reflects the brand image of the organization as well professionals written the documents, Written document/Investigation avoid the error from verbal spoken…thorough investigation document has to be embedded with the following minimal essential elements of technical writings;

• Correctness and Accuracy of document
• Consistency in writing
• Clarity from beginning to end
• Completeness of document
• Usability throughout the life cycle of document

STEP-4: VERIFYING (RE-DO): -

Verification is a thorough review of data by the 2nd subject matter expert to cross verify any shortcomings, specifically the interpretations and judgment drawn so as to improve upon the investigation report, the depth of the review is based on case to case basis, data can be verified against the raw data, meta data, experimental study and any other relevant data with their cross linkage. This is a micro –level review provides an opportunity to strengthen the investigation report.

This stage can suggest going back to previous stage, if the conclusion drawn is inconclusive or ambiguous, also this stage can recommend further course of action to generate some more hypothesis /experimental data to connect the dots with problem, cause and CAPA concluded.

STEP-5: CLOSURE (COMPLETENESS): -

This step requires a simple pre-requisite or checklist-based verification to ensure completeness of investigation document and its relevant raw data, missing items should be corrected, if any. Further this shall ensure the completeness of investigation in order to move on to next stage of CAPA effectiveness check. 

SUMMARY & CONCLUSIONS: -

The regulation outlines explicit expectations in embedding five basic pre-requisites within an investigation process must be “Thorough, Timely completed, Unbiased, Well-documented & Scientifically sound”.

While the intent of regulatory agency’s is to safeguard the patients and avert them to receive sub-standard drugs , this further encourages pharmaceutical professionals to think thorough keeping end purpose in mind and decision to pass or fail the batch is not merely a technical requirement , which has to go much beyond to uncover all other elements with equal importance to evaluate how a judgment is backed by sound principles of evaluating in terms of statistical variance and degree of acceptable error in addition to considering legal /regulatory commitment as well. 

While there is need of hour in up-skilling the professionals on few key elements as summarized below , paradigm shift in the intent of approach can surely bridge the shortcomings falling out due to;

• Shortcomings in technical-writing skills possess in art with conceptual clarity on the subject
• Tacit competency on the subject in understanding principles & purpose in full
• Analytical ability to interpret the data and conclude inferences,
• Understanding the degree of natural/inherent or random error and whether they are acceptable
• Inappropriate use of mathematical & statistical tools and interpret the data,
• Understanding inherent capability of process and analytical operations and finally,
• Understanding legal aspect of investigation and its repercussions rather viewing just a technical aspect.  

PS: Last but not least , no one is born as technical writer or investigator and one can groom up the skills with regular practice, hard-work with focused consistency , would suggest to go and write on as many as more than 1000 investigations to have mastery over the subject.