#GMP #Cleanrooms & Cleanroom #HVAC: A Practical Approach

Identifying the most practical approach to achieve Good Manufacturing Practice (GMP) cleanrooms and cleanroom HVAC in the pharmaceutical industry does not require an “out of the box” or innovative approach. It rests, rather, on the comprehension of and adherence to a set of basic rules that have been penned by several GMP regulatory authorities. Rules are nevertheless open to subjective interpretation and herein lie some potential pitfalls. The International Society for Pharmaceutical Engineering (ISPE) provides invaluable and much needed guidance in this regard.

The most commonly used GMP regulations that govern the design of pharmaceutical cleanrooms and cleanroom HVAC systems include the EU GMP, PIC/S GMP, FDA cGMP, and WHO GMP.

What is clean and how particlebased cleanliness is specified depends on what standards are applied. The world community of cleanroom designers mostly follows the ISO 14644 standard family for this purpose. Cleanroom designers and builders should concentrate on the first five parts of the standard family depicted in Table 1.

ISPE has provided a set of tools that facilitates a clearer understanding of the application of di€fferent GMP regulations, standards and guidelines in everyday work. Without these baselines it would be difficult to find suitable solutions to GMP matters. ISPE creates a bridge between pharmaceutical engineers and regulative authorities by writing baselines, good engineering practices and monthly articles in its ”Pharmaceutical Engineering” magazine.

The ISPE publication series includes ISPE Baselines, ISPE GAMP Guidance documents, ISPE Guides and Good Practice Guides, ISPE Investigational Products Resources, and ISPE Regulatory. This excellent source of reference information combined with engineers’ practical experience allow most clients’ GMP related questions to be solved. Local laws and codes naturally have to be applied in every aspect in order for project goals to be fulfilled. Once a project has started the ISPE general V-model should be followed (see Figure 1)

According to the V-model all GMP projects should start with a properly executed risk assessment based approach which leads to the appropriate Validation Master Plan (VMP) and finally to project-specific User Requirement Specification (URS). All GMP cleanroom projects should follow this generally accepted route:

Every phase has to be approved and completed with documented confirmation before proceeding to the next phase. It all starts from the user requirements and ends with the very same user requirements. All requirements in the URS need to be fulfilled or approved with documented deviations.

User requirements:

When the URS for cleanrooms or cleanroom HVAC is written in the conceptual design phase by the plant operator (often with engineers’ assistance) and approved, one can proceed to the basic design phase (or the functional design). the URS is arguably the most important document in the whole GMP project as it defines all the users’ (GMP) critical demands for the process, clean utilities, cleanrooms, cleanroom HVAC and black utility. URS in the GMP context means a documented definition of the key requirements stated by the user.

The URS must state what GMP regulations should be followed and what cleanliness grades are required. EU GMP and FDA cGMP requirements are the two mostly referred to but also WHO and Japanese regulations can be used if applicable.

Cleanrooms can be constructed in various ways, but the first thing that has to be solved is the layout, which is governed by basic rules. Figure 2 displays the main principle of a shell-like barrier system where the cleanliness grades are always separated by personnel airlocks, material airlocks or pass-through cabinets.

Layout design should only be started once a clear understanding of the user requirements has been gained. The basic rules for airlocks and pressure cascading regimes should, however, be checked first. Here again ISPE has some useful models. See Figure 3 (overleaf ) for a layout with cleanliness grades and pressure cascading.

There are some diff€erences in cleanliness grades between the US and EU which need to be kept in mind when designing cleanrooms for diff€erent regulatory environments. US GMP covers three cleanliness grades: supporting clean areas in two grades and critical areas. EU GMP includes four cleanliness grades: A, B, C and D. This di€fference aff€ects design especially when sterile drugs are produced in aseptic processing.

The crucial role of HVAC:

Once layout work is completed the HVAC designer can begin working. HVAC is only a small part of a cleanroom – but a very important part. Without a well-functioning HVAC system the desired conditions for production might not be achievable. HVAC systems for cleanrooms are relatively expensive and take up much space, but are essential for the critical product parameters.

HVAC systems also represent large operating costs. It firstly needs to be decided what type of ventilation principle would best satisfy the URS requirements: recirculated air or outside air? Recirculated air means a ventilation system where e.g. 80% of air flow is in constant circulation and only 20% is replaced with fresh air from outside. A 100% fresh air system uses non-recirculated air from the outside.

It is preferable to use recirculated air in a cleanroom ventilation system if it is not prohibited for any reason as the use of recirculated air reduces energy consumption and emission levels. Direct and indirect impact systems

It is of critical importance to determine whether the HVAC system has a direct or indirect impact on the product. According to the ISPE guidelines a direct impact system “is expected to have a direct impact on product quality. These systems are designed and commissioned in line with Good Engineering Practice and in addition, are subject to qualification practices that incorporates the enhanced review, control, and testing against specifications or other requirements necessary for cGMP compliance.” ISPE indicates that an indirect impact system “is not expected to have a direct impact on product quality, but typically will support a direct Impact system. These systems are designed and commissioned following Good Engineering Practice only. Indirect impact systems can affect the performance or operation of a direct impact system.”

Once the impact type of the system has been determined, the appropriate commissioning and validation activities can be applied.

Critical parameters:

The so-called critical parameters for products manufactured in a cleanroom environment need to be specified in the URS. According to the ISPE guidelines there are several factors that need to be considered and the onus is on the designer to gather all the relevant information (see the info box for details):

Validation of cleanrooms and cleanroom HVAC:

The first validation activity in cleanroom and cleanroom HVAC projects is the DQ whereas the last is the approval of all the required design documents. When everything is complete a design qualification (DQ) report is drawn up and signed. It is a generally applied approach that construction work cannot be started before design qualification is done.

The next step is construction, which is followed by commissioning (C), installation qualification (IQ), operational qualification (OQ) and finally performance qualification (PQ). Each has to be approved before the next step can start and approval of all steps has to be documented.

ISPE defines commissioning as a “well planned, documented, and managed engineering approach to the start-up and turnover of facilities, systems, and equipment to the end-user that results in a safe and functional environment that meets established design requirements and stakeholder expectations”.

Validation on the other hand “ensures that the facility and system qualification (DQ, IQ, OQ and PQ) requirements are communicated and met.”

Learn From FDA & MHRA GMP Inspection Observations

A comprehensive GMP intelligence program includes monitoring of enforcement actions, including FDA form 483s, warning letters, recalls, import alerts, consent decree agreements, EU reports of GMDP noncompliance, and inspection summaries published by selected European health authorities. This article presents the most recent GMP inspection data from CDER and MHRA (Medicines and Healthcare Products Regulatory Agency).  The CDER data and the MHRA data come from GMP inspections conducted in 2016.

The CDER drug inspection observations supplement the information we published in a previous article regarding CDER drug GMP warning letters from the same time interval.  The analysis herein includes data from the FY2016 form 483 observations and compares results with those from the three previous fiscal years. Raw data comes from the FDA website, though it is presented in a different manner. For example, I have combined the frequencies of all observations that cite 21 CFR 211.192 into a single value. In the FDA data, there are multiple line items for 211.192, each with a different frequency.  For example, in the FDA listing the most frequently cited item is 211.22(d), procedures not in writing, fully followed.  When you combine the full collection of times that 211.192 and 211.42(c) are cited, however, they become tied for No. 1, with 211.22(d) becoming the third most frequent citation.  FDA uses the term “frequency” which seems to be the number of times a given citation was identified in the form 483 collection supporting these data. 

Only form 483s that were issued through the Turbo EIR (Establishment Inspection Report) system are considered in this data, which provides a distinct limitation.  No form 483s issued to API manufacturers or issued outside of the Turbo EIR system are included. This becomes important to consider with FDA’s increased focus on API manufacturers, particularly outside the U.S.   MHRA data is similar and only includes deficiencies identified at dosage form manufacturers.  Note that the MHRA data includes only the 10 most frequently cited groups, whereas the data on the FDA website includes all observations. 

Here are some highlights of the analysis:

FDA:

The number of form 483s included in this analysis remains reasonably constant over the past four fiscal years even though it does not represent all drug inspections conducted by the FDA, particularly inspection of sites that manufacture APIs.

Deficiencies in investigations remains at the top of this list over the past four years.  We as an industry cannot seem to get this quite right.

In general, the regulations cited and their relative order has remained reasonably constant over the past four fiscal years.  Even though a few items have changed place, none of the numbers are striking.

MHRA:

MHRA issued 143 “critical” deficiencies, in a total of 324 inspections of which 82 inspections (25 percent) were overseas inspections and 242 inspections (75 percent) were conducted in the U.K.

The EU GMP Guide Chapters and Annexes that were cited in critical observations include, in order of their frequency: Chapter 1, Annex 1, Chapters 5, 8, Annex 15, Chapter 3, Annex 11, Chapter 2, Chapters 4 and 6.  

The MHRA cited a total of 4,588 deficiencies in the 10 areas that received the critical observations.  Critical deficiencies constituted 3 percent of the total.

The sections that follow include more detailed discussion of the observations.

FDA Form 483 Inspection Observations

The following data is based on inspections generated using the FDA Turbo-EIR system.  The number of form 483s remained quite similar over the four years in question, with FY2014 having the fewest.  Form 483s issued to API manufacturers or issued outside of the Turbo EIR system are not included.

Table 1 shows only the most frequent group of inspection observations; the tabulation on the FDA website shows all observations.  Table 1 is organized in the order of those observations with the highest to lowest frequency for 2016.  In several instances, though, the order of the observations did change in FY2016 from previous years; these are highlighted in gray. 

Table 1: Inspection Observations Issued Through Turbo-EIR System per Fiscal Year. (These are shown in the order of highest to lowest for FY2016.)

Figure 1 below shows the data from Table 1 graphed over four fiscal years, 2013–2016.  While there is some variation from year to year, the frequency with which specific regulations are identified remains generally constant.  Figure 2 shows additional detail of several of the areas where the frequency of the observation did show some variation between FY2015 and FY2016.

Figure 1: Frequency of observations

Figure 2: Selected observation frequency

In conclusion, there is little change in the overall frequency of inspection observations, as characterized by the regulation cited, between FY2013 and 2016. This may have been different if all inspected sites, including API sites, had been included in the metrics. The three most frequent observations in FY2016 cite 211.192 (investigations), 211.42(c) (design of facilities to prevent cross contamination), and 211.160(b) (scientifically sound specifications). While 211.192 was in first place for all four fiscal years, in 2016 it tied with 211.42(c), Requirement for adequate facilities to prevent contamination or mix-ups, moved up from third place, even though the actual number of those observations decreased from 2015. Citations against 211.160(b) Development of scientifically sound specifications went from second place to fourth place. Observations citing 211.113(b) Validation of aseptic processes including sterilization dropped from fifth place to sixth place in 2016, and the actual number decreased significantly, to FY2013 levels. Finally, observations identifying 211.25(a) Staff shall have training, education and experience to perform their jobs dropped from eighth place to 10th place in 2016. 

MHRA Inspection Deficiencies

I won’t reproduce the graphics from the MHRA slide deck, but I do recommend reading those because they contain a wealth of information at a granular level. The MHRA conducted a total of 324 inspections in 2016; 242 inspections were conducted in the U.K. and 82 inspections were conducted overseas. The MHRA inspections identified 143 total “critical” deficiencies in 2016, a dramatic increase from 2015 when 51 were identified. We cannot compare this with the U.S. FDA inspection observations because the FDA does not classify the criticality of observations. In the future, perhaps health authorities will adopt a common classification category for inspection observations.

MHRA identified critical deficiencies in only five areas in 2015, and increased this to 10 areas in 2016. Several categories saw significant increases, for example:

• Sterility Assurance had no critical observations in 2015 and 34 in 2016
• Personnel had no critical observations in 2015 and eight in 2016
• Premises and Equipment had no critical observation in 2015 and nine in 2016
• Computerized Systems had one critical observation in 2015 and nine in 2016.

Table 2 identifies the areas with critical deficiencies identified in 2016. The groups included seven Chapters and three Annexes. Figure 3 clearly shows that approximately two-thirds of the deficiencies are included within three groups: Quality Systems, Sterility Assurance, and Production.

Table 2: Chapters and Annexes Associated with MHRA Critical GMP Inspection Deficiencies in 2016

                          Figure 3: Distribution of these critical MHRA deficiencies

Conclusions:

It is difficult to directly compare areas identified by the MHRA with those identified by the FDA, as the FDA does not categorize the criticality of inspection observations as do the MHRA and other health authorities. We can, however, say that with FDA observations addressing “investigations” at the top of the list, “quality unit responsibilities” third on the list, and “staff training” at No. 10, quality systems is a high priority for the FDA. Similarly, Quality Systems is the area with the most critical deficiencies identified by the MHRA in 2016. Validation of aseptic processing (21 CFR 211.113(b)) was sixth on the FDA list but was second on the list for MHRA.

Computer system requirements are identified in Annex 11, Computerized Systems. Data integrity and data governance deficiencies are identified by MHRA by citing either Chapter 4 or Annex 11, both of which were associated with critical deficiencies in 2016. Similar FDA regulations are found in 21 CFR 11, Electronic Records; Electronic Signatures, and it is rarely, if ever, identified in either form 483s or warning letters. The FDA frequently associates these types of inspection observations with predicate rules including 21 CFR 211.68(b) and 21 CFR 194.

MHRA has always had a reputation as one of the most rigorous health authority inspectorates. It seemed to have upped its game in 2016, as demonstrated by an increase in the number of critical deficiencies, along with an increase in the total number of deficiencies identified for essentially the same number of inspections.

Both agencies will likely continue to focus on sterility assurance, investigations, quality systems, and data integrity/governance in 2017. It would be interesting to see if the number and types of observations identified during API inspections were similar for the two health authorities. And finally, the Mutual Recognition Agreement (MRA) between FDA and the European Medicines Agency will likely not impact the number of inspections for 2017, though it may be possible to see that happen in 2018. Time will tell how this impacts the number and locations of both EMA and FDA inspections.

References:

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/582841/MHRA_GMP_Inspection_Deficiency_Data_Trending_2015.pdf

- Barbara Unger

Fundamental Elements of 21 CFR Part 11 & GMP Annex 11

Along with providing monitoring and validation systems, we often delve into issues that arise for our customers when they are interpreting regulations and guidance. We receive many questions on 21 CFR Part 11 and Annex 11.  In this article we we offer some background and a brief overview of three focal points of both of the "Elevens"  including:  System Controls, Validation and Archiving.

It's important to note that Part 11 is a requirement in the US, whereas Annex 11, which applies to the EU, is a guidance document only. By the way, we are assured by those in the know that the "11" in the titles are  incidental. Someone please correct us if we've been misinformed!

Background:

Computerised systems — crucial to pharmaceutical, medical device, and biotechnology manufacturing and distribution operations — differ from paper-based systems and  manual systems traditionally used for creating and archiving records are becoming rare. 

This is (partly) why the FDA and EMA  created 21 CFR Part 11 and Annex 11. But the real basis for of "the elevens" is to ensure that the quality and safety of drugs and biologicals do not suffer as a result of computerized systems replacing a manual system.  

 Annex 11 states:

"Where a computerized system replaces a manual operation, there should be no resultant decrease in product quality, process control or quality assurance. There should be no increase in the overall risk of the process." 

The FDA similarly says that the purpose of Part 11 is to make sure electronic records are: 

"...trustworthy, reliable, and generally equivalent to paper records."

The FDA's statement entails the fact that for generations, paper records were all we had to depend upon to ensure that processes and conditions that preserved the safety and quality of drugs were performed properly. 

Both Part 11 and Annex 11 remind us of the importance of safety, and address the need to set up standards to make ink and electronic or digital signatures equivalent in their effect.

Controls: Human Readable, Unmodifiable, Authorized 

Both Part 11 and Annex 11 include the following elements: 

• Validation

• Human Readable Copies

• Protection and retention of records

• Audit trails

• Restricted access for authorized users only

• Authority checks

• Device checks

• Training

• Written procedures

• System documentation

One glimpse at the list shows that each is in some part a method for controlling the function and outputs of a system. 

In 21 CFR Part 11  "Controls for Closed Systems" states: 

(b) "The ability to generate accurate and complete copies of records in both human readable and electronic form suitable for inspection, review and copying by the agency."

The fact that there is a specific regulation regarding human-readable copies demonstrates how far technology has evolved.  It would be hard today to imagine a user-friendly system that did not allow for the printing of documents and data.   

For most monitoring systems, the records of interest are the actual historical monitoring values.  And  creating a human-readable copy likely means that historical data and event logs may be printed out in a secure format.

In 21 CFR Part 11 (e) in "Section 11.10 - Controls for Closed Systems we read: 

"Use of secure, computer-generated, time-stamped audit trails to independently record the date and time of operator entries and actions that create, modify, or delete electronic records. Record changes shall not obscure previously recorded information. Such audit trail documentation shall be retained for a period at least as long as that required for the subject electronic records and shall be available for agency review and copying."

In terms of your environmental monitoring  applications, this simply means that, in order for your records to comply, the electronic records (data and events) cannot be manually modifiable or deletable.

In addition, the Audit Trail of your system needs to capture any changes to metadata (schedules and report templates) and configuration data without obscuring earlier entries.   If your system doesn’t allow any changes to values once recorded, it complies with those sections of both Part 11 and Annex 11.

As a closed system, your monitoring system needs to limit access to only "authorized individuals." That's item (d) in Section 11.10 of Part 11. Typically this means that all who have access to the system have a distinct username and secure password. Often a system will integrate with your OS authentication to leverage commonly used, pre-existing password management tools. 

Validation: Prove it Works & Document your proof

With regard to validation, Part 11 lays out the need for validation in the first item of Section 11.10: "Controls for Closed Systems":

(a) "Validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records."

In Annex 11, the "Project Phase" section covers validation in  eight fairly brief, fairly straightforward points: 

Use risk assessment to justify standards, protocols, acceptance criteria, procedures and records

Use correct change control documentation practice to report deviations

Keep an Inventory of your computerised systems with descriptions, interfaces, processes, software and hardware

Use risk assessment to assess the GMP impact of User Requirements Specifications 

Audit suppliers’ Quality Management Systems

Validation of computerised systems covers the entire life-cycle of the system 

Document testing 

Validate data transfers

We see that Annex 11 is more explicit in recommendations for validation. 

Archiving: Validated, Secure, Accessible

The protection and retention of records, as described in Part 11's Section 11.10 (c) means that whatever data your system produces, it may not be altered.  In addition, to meet the requirement of "ready retrieval throughout the records retention period," your data needs to be archived in a way that it can be conveniently accessed – you don’t want to make an auditor wait, 

If you store the data permanently within your database, the database should be designed in such a way system's performance should not degrade as the database grows over time.  How you meet this requirement of 21 CFR Part 11 may have as much to do with the design of your system as it does with your system administration policies around archival.

In Annex 11 under “Data Storage” it is recommended that data be securely stored, and backed up BOTH physically and electronically and regularly checked for accessibility, readability and accuracy.  Annex 11 also mentions is the need to validation data restoration abilities of the system. 

Part 11 and Annex 11 were introduced to address the key differences between computerized and manual systems and make electronic records equivalent to paper records as evidence of quality process execution. Today, most environmental monitoring systems used in GxP compliant firms are inherently aligned with the requirements of both the "Elevens." However, the risk comes not from the systems themselves, but in how they are implemented and maintained. 

Although your monitoring system probably included User and Administrator manuals and CDs that are fairly easy to integrate into your Document Management System, the procedures that control documentation are still your responsibility.  As good as your monitoring system may be (and, if you have a Vaisala system, it's awesome!), only the procedures of your Quality System keep you in compliance with Part 11/Annex 11. 

We didn't cover Electronic Signatures because that's a specialized software function. Specialty enterprise software exists for implementing Electronic Signatures within an Electronic Document Management System (EDMS).  For Vaisala's monitoring solution, we use a "hybrid" system, which means it uses electronic records combined with handwritten signatures, wherein the PDF outputs can be imported into and EDMS. 

Validation Strategies For Nonsterile Solid Dosage Forms

Process qualification, which includes pharmaceutical drug products at a stage prior to commercialization or prior to submitting a New Drug Application (NDA) or Abbreviated New Drug Application (ANDA).  In this stage, it must be demonstrated that the process for manufacture of a drug product is consistent and can produce drug products that are compliant with the Food and Drug Administration’s requirements for filing. 

This stage includes two elements.  The first element focuses on facility design and equipment installation and maintenance while the second includes process performance qualification (PPQ).  Some prerequisites to facility design and equipment installation and maintenance includes validation and qualification of analytical methods, approved standard operating procedures (SOPs) for process validation, implementation of preventive maintenance program (PMs), cleaning validation of equipment, and process specific GMP training.  In structuring a PPQ, CPPs and CQAs must be defined, justified, and documented.  Other process performance qualification activities must be controlled by an approved protocol that includes the scope, strategy, testing, sampling plan, and acceptance criteria. This study is conducted at a manufacturing site, according to a site validation master plan.  Additional strategies are explored below.

Process Qualification Study Strategies:

A strategy needs to be developed for every qualification study and it must be based on deep process understanding gained from the manufacturing experience. Some elements to consider include:

1. Number of Batches: The protocol should include three consecutive batches, with the results summarized in the final process qualification report.

2. Material Selection:  Selection of more than one lot of API and critical raw materials should be used during process qualification (especially if the API or critical raw materials are not dissolved or distributed in solution). Based on the selection of these materials, a process should be designed to validate the robustness of the process.

3. Equipment Selection: The process must be qualified on all equipment intended to be used in the manufacture of the product. For equipment determined as being equivalent, qualification on one piece of equipment is sufficient.

4. Design Space/Parameters Ranges:  For products that have an established design space, the process qualification should be executed at specified conditions within the design space. For conditions that are high risk, high and low parameter ranges should be considered for the process qualification.

5. Process Re-qualification:  Process re-qualification may be required if, for example, a significant deviation from desired process performance is uncovered through stage 3 continued process verification.  The process re-qualification studies should bridge back to the original or pivotal clinical biobatch.

Process Qualification Testing:

Process qualification testing should be based on the established CPPs and CQAs and the control strategy and risk assessments, which characterize the product quality and process consistency.

CPP Monitoring:  Defined critical process parameters should be monitored and reported in the final qualification report.

• For processes that have a processing fluid (e.g., granulation), microbial testing and hold times will need to be established. For processes where critical ingredients are added as a part of the processing fluid, testing related to the critical ingredient (e.g., assay) at make-up and at the end of hold time should be considered.  
• For processes involving lubricated granulation, blend uniformity testing must verify that the active ingredient has been distributed throughout the blended bulk uniformly. To determine unit-dose equivalent (1-3x) blend uniformity of the active ingredient on the final, blend samples should taken from the blender. For combination products, all APIs need to be tested for blend uniformity while respective blenders need to be tested for bilayer tablets.
• For the manufacture of compressed tablets or capsules, during the compression operation a sampling plan should be adopted with around ten evenly spaced intervals throughout the batch processing. After the compression machine is set-up, location one should include the first salable dosage units and location ten should contain the last salable dosage units while location two through nine should be evenly spaced across the lot.  For a process using a double sided machine, both the sides of the machine should be sampled at each location. For the manufacture of combination or bilayer tablets, ample samples should be obtained to properly evaluate all API specific tests.  Specific to bilayer tablets, samples should be taken to evaluate both layers.
• For the manufacture of film coated tablets, random location sampling should be taken of representative samples. For application of functional membranes, testing should be performed on samples taken from each film coating pan load. For nonfunctional coats, samples may be divided among the film coating pan load.

Acceptance Criteria:

The manufacture process must be validated and reported within the regulatory filing, batch records and final validation report, including all the appropriate specification and procedures (e.g., selected CPPs and release requirements). Any deviation must be investigated and addressed in the validation report. 

Each of the processing steps can be analyzed by evaluating the process control charts (based on three sigma limits) and the historical process capability charts.  These charts should be evaluated for nonrandom systematic behavior.  Ultimately, for all initial process qualification, a comparison must be made to the dissolution profile performed on the biobatch or pivotal reference batch.  A batch may be excluded if a nonprocess related assignable cause, like mechanical failure, has been identified.

Statistical Analysis:

Intra-batch and inter-batch variability should be examined from data collected during process qualification through the analysis of process control charts and process capability charts.

Once a product has completed performance qualification, process validation continues through implementation of continued process verification.  This verification includes monitoring operating procedures, preventive maintenance and calibration programs, deviation investigations, annual review, and change control procedures. Any changes to the process must be evaluated through the process change request system and procedures for process change control to determine the impact to on-going process validation.  A list of intermediate tests for nonsterile solid dosage forms (tablets and capsules) are compiled in Table 1.

Stage 2 process qualification is conducted at the manufacturing site, which is usually a far distance away from product development/process development facilities. Therefore, another important piece of the process validation includes technology transfer to manufacturing facilities. Technology transfer includes detailed process fit, manufacturing readiness, and an execution phase. Process qualification falls under the execution phase.

Continued Process Verification (Stage 3)

The goal of continued process verification (CPV) is “continual assurance that the process remains in a state of control (validated state) during commercial manufacture.”[5] Once a process has gone through process qualification, an ongoing program to collect and analyze product and process data that relate to product quality is necessary. The objective of the on-going process verification program is to understand the sources of variation, its impact on the process and product attributes, and finally to devise a way to control the variation. The knowledge gained through stage 3 of continued process verification provides ongoing assurance that a product remains in a state of control.

In summary, QbD is not a mandated requirement, however, any pharmaceutical company that instills the QbD approach in their DNA of product development (process design, process qualification, and continued process verification) will come out ahead in their value curve, since we live in an increasingly science-driven regulatory environment in 21st century — where compliance and quality have been essential elements of competitiveness and quality drug products. Hopefully these tips and strategies will support you in designing and validating a quality manufacturing process.