Guest Column | May 31, 2024

Defining And Overcoming Batch Release Deviations

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In the pharmaceutical environment, as in any process industry, situations can arise where processes or specifications cannot be met or lead to unexpected or deviant results. It is critical to respond to such situations in a controlled manner to understand and evaluate them, to address the root causes of errors, and to prevent errors in the future.

There are many different contexts for use of the term "deviation." No clear, sharply outlined definition can be found in the various regulatory documents in the U.S. or the EU. The terms used are not always the same either (for example, deviation, discrepancy, atypical situation, non-conformity).

Therefore, it is imperative for a company to define internally what is understood by the term deviation, to avoid vagueness and possible misunderstandings concerning workflows and responsibilities.

The term “deviation“ must be defined individually in each company.

In the narrower sense of the word, deviations represent a failure to meet specifications (such as parameter settings) in the production process, in-process specifications, or production requirements. In a broader sense, however, deviations from other procedures or instructions can also be assigned to the deviation system. Depending on how the deviation system is interpreted in any given company, confirmed out-of-specification laboratory results (OOS results), for example, can also be introduced into the deviation system. The advantage of such a comprehensive structure is that relevant data from different areas can be gathered jointly and subjected to a comparative evaluation.

A fundamental distinction can also be made between batch-specific and non-batch-specific deviations (Figure 1). Deviations, which occur, for example, in manufacturing processes, will directly affect batches and thus have a possible influence on the product quality. But also in the case of non-batch-specific deviations, e.g., within the scope of environmental monitoring cleanroom Grade C or D, the possible influence on individual batches must be evaluated within the scope of the investigation.

Batch-specific deviations
  • Deviations from, e.g., process instructions, manufacturing and packaging instructions, product specifications
  • Possible influence on the product (safety, quality, identity, purity, content, etc.)
Non-batch-specific deviations
  • Deviations in general systems, e.g., ventilation systems or water systems
  • Results in room monitoring (not accompanying batches)
  • Possible influence on batches must be investigated.

Figure 1: Classification into batch-specific and non-batch-specific deviations

What Is Not A Deviation?

It has proven to be a good practice to also clearly indicate in which areas of the company the deviation management does not apply. This will be illustrated with a few examples:

Monitoring systems

The distinction "When is there a deviation?" can be explained well in the case of monitoring systems. Let us consider as an example the exceeding of warning limits when monitoring the quality of water systems, e.g., an increase in TOC values determined online. Although the results should be considered and investigated systematically, exceeding warning limits should not be regarded as a deviation in terms of deviation management. In this example, only exceeding the alarm limit would be treated as a deviation.

Event management

Similarly, the use of another process in the quality system can be considered. Here, so-called "events" (also incidents, observations) are used as system elements. These events are recorded and evaluated in a simplified form and, if necessary, upgraded to a deviation.

Equipment qualification

Another example is the handling of deviations from specifications or acceptance criteria in the qualification of machines. In this example, the validation master plan defines how deviations are dealt with. The following questions must be answered.

  • Who assesses the criticality and the resulting risk of the deviation?
  • How is this assessment performed and documented?
  • Who approves this assessment?
  • After completion of a qualification phase (e.g., IQ), can the qualification activities (e.g., OQ) be continued even though there are deviations (e.g., documents still missing)?
  • What measures must be taken to be able to accept the risk?
  • How is this taken into account in the final assessment?

Independent systems

Other examples of processes commonly used in systems other than deviation management are:

  • audit observations
  • complaints
  • recalls
  • pharmacovigilance observations
  • production of investigational medicinal products Phase 1

What Is A Planned Deviation?

Deviations are inherently unplanned. They occur spontaneously and represent individual cases.

In non-European countries, the term planned deviation is often used. This particularly applies to short-term deviations or changes to procedures and processes, which are to be carried out only once in a controlled manner, e.g., within the framework of experiments. Examples can be additional sampling in the manufacturing process or the risk-based use of a starting material without completed release tests (e.g., due to pending microbiological results). These so-called planned deviations are also called temporary changes. The following conditions must be met:

In Germany, the authorities have decided that the term “planned deviations“ should, by definition, no longer exist. In other EU countries, this is less strictly applied, but the trend is the in the same direction. In the U.S., by contrast, planned deviations are widespread, established, and accepted.
  • Planned deviations must be limited to individual cases or specific time periods.
  • In principle, the same requirements regarding risk assessment and any additional risk minimization measures to be taken as for unplanned deviations must be met.
  • It is important to distinguish between a change within the scope of change control and deviation management.

A so-called temporary change/deviation does not replace the change control procedure. If different electronic systems are used, the temporary changes could technically be operated in both the deviation management system and the change management system if the workflow is defined accordingly. Due to the rather prospective risk assessment, change management is particularly suitable.

Figure 2 compares important features of deviations, changes, and planned deviations or temporary changes.

  Deviation Planned deviation/
temporary changes
 
Change
Occurrence Spontaneous Planned Planned
Duration One-time One-time or limited Permanent
Documentation Notification and report Application and approval Application and approval
QS System Change management Change management (if applicable, deviation management) Change management
Risk management Retrospective Prospective Prospective
Adjacent systems Failure management, CAPA
QRM
QRM QRM

Figure 2: Important features of deviations, changes, and planned deviations/temporary changes

Dealing With Deviations During Batch Release

Annex 16 describes which requirements are placed on the QP when dealing with deviations in the context of release (Figure 3).

Requirements for handling unexpected deviations during batch release
Provided registered specifications for active substances, excipients, packaging materials and medicinal products are met, a QP may consider confirming compliance or certifying a batch where an unexpected deviation concerning the manufacturing process and/or the analytical control methods from details contained within the marketing authorisation (MA) and/or GMP has occurred. The deviation should be thoroughly investigated and the root cause corrected. This may require the submission of a variation to the MA for the continued manufacture of the product.

Figure 3: Requirements for handling of deviations during batch release according to Annex 16, Chapter 3

Requirements For The Release Of Batches With Deviations

Certification and release of batches with deviations is only possible if the core requirements in Figure 4 are met.1

The registered specifications are met.
This includes the registered specifications of active ingredients, excipients, packaging materials, and those of bulk and finished product. If these specifications are not complied with, the QP would not be able to certify/release the affected batch. For in-process controls, the individual risk must be assessed, e.g., depending on the quality attributes tested, the effect on subsequent production steps, and the possibility of testing the quality attribute on the finished product.
The deviation is unexpected.
Only unexpected deviations fall under the definition of Chapter 3 Annex 16. Conversely, this means that repeat deviations cannot be accepted because they are not unexpected. If a deviation is detected at a later stage in a manufacturing campaign, these deviations can still be considered as unexpected until the time of detection. Subsequent deviations are not acceptable and should be submitted as variations to the MA. Exceptions to this can only be accepted if this is approved by the authorities in order to avoid supply disruption and the implementation of actions (CAPA) is in progress.
The deviation relates to the processes and methods in manufacturing and testing from an approval or GMP perspective.
The deviations in production and quality control do not concern the registered specifications, but the production processes or analytical procedures described in the MA, or they are GMP deviations, such as non-compliance with instructions.
The deviation has been thoroughly investigated and its root cause has been eliminated.
The deviation has been investigated within the framework of the deviation management system, the root causes have been determined and the effects with regard to their risk have been examined within the framework of quality risk management. Actions have been initiated accordingly.
Impact on quality, safety, or efficacy is negligible.
It must be shown that the possible impact on the quality, safety, or efficacy of the batch or batches concerned is either nonexistent or negligible. This is an elementary evaluation within the deviation management.
The need for a stability study has been assessed.
Consideration must be given to whether a stability study is neccessary for the affected batch(es) to detect possible effects of the deviations on the stability of the product.
For biological medicinal products, all deviations have been evaluated.
For biological medicinal products, special reference is made to the fact that any deviation may have unexpected effects on safety and efficacy, thus taking into account the higher complexity.

Figure 4: Requirements for the release of batches with deviations

If the above conditions are met, the QP may consider certification and release despite deviations. The rationale for the decision must be documented in a comprehensible manner. If multiple QPs are involved in the manufacture, control, or certification of the batch, the final certifying QP must be aware of any deviations from regulatory or GMP compliance. This is usually described in the respective quality agreements. One possible way is to list the deviations in the respective certificate of compliance for the individual manufacturing step.

This article is an excerpt from GMP knowledge contained in the online portal GMP Compliance Adviser, which provides in-depth information about GMP best practices and regulations with a focus on Europe but also referring to the U.S., Japan, and many more (PIC/S, ICH, WHO, etc.).

Reference:

  1. Chapter 3 of Annex 16 and explanations in Guidance on good manufacturing practice and good distribution practice: Questions and answers, EU GMP Guide annexes: Supplementary requirements: Annex 16 (Updated May 2018)

About The Author:

Christain Gausepohl is a global quality director and qualified person responsible for quality and compliance issues. He has worked in many different positions and has extensive audit and inspection experience with authorities, customers, and suppliers. His main concern is the practical implementation of GMP requirements.He started his professional career in galenic development in 1998 after graduating in pharmacy and receiving his Ph.D. in pharmaceutical technology. He held managerial positions in production, validation and technology transfer, was responsible for quality assurance and quality control, and was strongly involved in developing a robust QM system. In 2013, he took over the entire quality unit. He works for national and international organizations and associations and lectures on issues that affect the practical implementation of GMP requirements. Reach him at christian.gausepohl@outlook.com