Category Archives: Validation

Compliance in the Cloud: ISO 27001 Information Security Management Systems

Hello good people of the world! Today’s post is continuing the series on compliance in the cloud. In the last post, we looked at the FDA’s 21CFR11, which is the legal statute medical device, pharmaceutical, and biologic manufacturers must adhere to when using computer systems for electronic records and/or signatures as part of their manufacturing process for products sold in the United States.

But 21CFR11 is old (1997!) and vague, really only covering at a high-level the requirements for impacted computer systems. Industry has filled in the details, and the ISO standards are a good example of that.

ISO 27001 covers Information Security Management Systems and costs about US$130. Firms may reference ISO certification as evidence of 21CRF11 compliance, such as Microsoft’s statement here.

Below is a summary of the procedural and/or engineering controls required by the standard. You’ll see a lot of overlap with the CFRs, other industry guidance like GAMP5, and other regulations like MHRA’s data integrity expectations.

Management of Policies

  1. Policies shall be defined, approved by management, and distributed to employees.
  2. Policies shall be reviewed at a planned interval and must be revised when processes change.
  3. Responsibilities shall be defined.
  4. Duties shall be segregated to avoid conflicts of interest.
  5. Communication with relevant authorities shall be maintained.
  6. Communication with relevant special interest groups and forums shall be maintained.
  7. Information security shall be addressed in all projects.

Human Resource Security

  1. Background checks shall be employed.
  2. Responsibilities related to information security shall be documented and understood.
  3. Training relevant to job functions shall be mandated and documented.
  4. A formal disciplinary process shall exist for employees who have committed an information security breach.
  5. Responsibilities shall be managed appropriately upon employee termination.

Asset Management

  1. An inventory of assets shall be maintained.
  2. Each asset shall have an assigned owner.
  3. Acceptable use of each asset shall be documented.
  4. Distribution and return of assets shall be managed.

Information Classification

  1. Information shall be classified in terms of legal requirements, regulatory requirements, confidentiality, etc.
  2. Procedures shall exist for the labeling of information by classification.
  3. Management of assets shall take into consideration the classification of information associated with the asset.

Media Management

  1. Removable media shall be managed per procedure.
  2. A procedure shall exist for the proper disposal of media.
  3. Procedures shall exist for the physical transfer of media, including protecting against unauthorized transfer, and damage/corruption of media during transfer.

Access Control

  1. A procedure shall exist for access control.
  2. User access shall be limited to the networks, systems, and information required to perform their job duties.
  3. A procedure shall exist for the registration and de-registration of users.
  4. A procedure shall exist for the access provisioning of users to all applicable systems.
  5. The allocation of privileged access rights shall be restricted and controlled.
  6. Authentication information shall be controlled through a formalized process.
  7. Asset owners shall review user access at planned intervals.
  8. User access shall be removed at appropriate times, such as employee termination.

Cryptography

  1. Procedures shall exist for the use of cryptographic controls to protect information.

Physical Security

  1. Security perimeters shall be defined to protect areas containing sensitive information.
  2. Secure areas shall employee physical entry controls.
  3. Physical protection against external and environmental threats shall be established.
  4. Procedures shall exist for working in secure areas.

Equipment

  1. Equipment shall be protected from problems with supporting utilities.
  2. Cabling shall be protected from interception, interference, and damage.
  3. Equipment shall be maintained on planned intervals.

Operations Security

  1. Operating procedures shall exist.
  2. Change management procedures shall exist.
  3. Resource use and process capacity shall be measured and understood.

Backup

  1. Backup and restore procedures shall be documented and tested on planned intervals.

Logging

  1. Event logs shall be employed, retained, and reviewed on planned intervals.
  2. Logs shall be protected from tampering, unauthorized access, and loss.
  3. Administration activities shall be logged and reviewed on planned intervals.
  4. Clocks used by systems shall be synchronized to a single reference time source.

Development Processes

  1. Software development procedures shall be documented.
  2. Changes to systems in the development lifecycle shall be controlled.
  3. Development environments shall be secured.
  4. Security functionality shall be tested during development.
  5. Acceptance testing shall be established for all new versions of software.
  6. Test data shall be controlled.

Suppliers

  1. Risks associated with supplier access shall be documented and mitigated.
  2. Risks and mitigations shall be communicated and agreed upon with suppliers.
  3. Suppliers shall be audited on planned intervals.
  4. Changes to supplier relationships shall be controlled.

Incidents

  1. Procedures shall exist for the management of incidents.
  2. End users shall be required to report incidents.
  3. Corrective and preventive actions shall be applied to the management of incidents.

Business Continuity

  1. Procedures shall exist for the continuity of business processes during adverse events.
  2. Business continuity procedures shall address information security concerns.

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Compliance in the Cloud: 21 CFR Part 11 Requirements

Hello good people of the world! Today’s post is the next in the series on compliant software in the cloud. Today we’re taking a deep dive into the FDA’s 21st Code of Federal Regulations, Part 11 (21CFR11). If you’re not familiar, 21CFR11 is an ancient (written in the late 1990s) regulatory statute on the use of electronic records and electronic signatures in regulated industries such as medical device, pharmaceutical, and biologic manufacturing. Despite it’s age, 21CFR11 is the governing statute for the use of computer systems in regulated spaces, so it’s critical that we understand it well.

In this post, I’ll give a abridged version of each applicable section of the statute, and then detail the engineering and procedural requirements that are typically used to meet the statute in the design, development, and implementation of a cloud-based computerized system. Let’s go!

Subpart B §11.10, Controls for Closed Systems

  • Persons who use closed systems to create, modify, maintain, or transmit electronic records shall employ procedures and controls designed to ensure the authenticity, integrity, and, when appropriate, the confidentiality of electronic records. Controls used require the following:
    • Validation
    • Legibility
    • Record Protection
    • Limited System Access
    • Secure Audit Trails
    • Operational System Checks
    • Authority checks
    • Device Checks for data validity
    • Training
    • Policies in place for operational adherence
    • Control of Distribution
    • Change Control Procedures

Engineering requirements:

  • System shall employ HTTPS and other modern web application security technology per according to ISO/IEC 27001 and ISO/IEC 27018 standards
  • System shall employ user-level security, ensuring each user is required to maintain a unique username and password to access the system
  • System shall employ role-based permissions and limit access to only functionality required by the job role
  • System shall employ audit trail to ensure compliant activities are documented with username, time/date stamp, and reason for signature
  • System shall employ electronic signatures with username, time/date stamp, and reason for signature for GxP-related activities

Procedural requirements:

  • System shall be validated
  • Audit trails shall be reviewed
  • Appropriate training shall be assigned and managed
  • Use and administration procedures shall exist
  • Change control procedures shall exist

Subpart B §11.50, Signature Manifestation

Requirements for signature manifestation:

  • Signed electronic records shall contain information associated with the signing that clearly indicates all of the following:
  • The printed name of the signer; The date and time when the signature was executed; and
  • The meaning (such as review, approval, responsibility, or authorship) associated with the signature.

These are subject to the same controls as for electronic records and shall be included as part of any human readable form of the electronic record (such as electronic display or printout).

Engineering requirements:

  • System shall employ electronic signatures with username, time/date stamp, and reason for signature for GxP-related activities

Procedural requirements:

  • System shall be validated
  • Audit trails shall be reviewed
  • Appropriate training shall be assigned and managed
  • Use and administration procedures shall exist
  • Change control procedures shall exist

Subpart B §11.70, Signature/Record Linking

Electronic signatures and handwritten signatures executed to electronic records shall be linked to their respective electronic records to ensure that the signatures cannot be excised, copied, or otherwise transferred to falsify an electronic record by ordinary means.

Engineering requirements:

  • System shall employ electronic signatures with username, time/date stamp, and reason for signature for GxP-related activities
  • Electronic signatures shall be linked to specific records and cannot be transferred by any means.

Subpart C §11.100, General Requirements

Each electronic signature shall be unique to one individual and shall not be reused by, or reassigned to, anyone else.

Before an organization establishes, assigns, certifies, or otherwise sanctions an individual’s electronic signature, or any element of such electronic signature, the organization shall verify the identity of the individual.

Persons using electronic signatures shall, prior to or at the time of such use, certify to the agency that the electronic signatures in their system, used on or after August 20, 1997, are intended to be the legally binding equivalent of traditional handwritten signatures.

  • The certification shall be submitted in paper form and signed with a traditional handwritten signature, to the Office of Regional Operations (HFC-100), 5600 Fishers Lane, Rockville, MD 20857.
  • Persons using electronic signatures shall, upon agency request, provide additional certification or testimony that a specific electronic signature is the legally binding equivalent of the signer’s handwritten signature.

Engineering requirements:

  • System shall employ user-level security, ensuring each user is required to maintain a unique username and password to access the system
  • System shall employ role-based permissions and limit access to only functionality required by the job role
  • System shall employ electronic signatures with username, time/date stamp, and reason for signature for GxP-related activities
  • Electronic signatures shall be linked to specific records and cannot be transferred by any means.

Procedural requirements:

  • Procedure shall exist for systems users to sign testimony that their electronic signature is equivalent to their handwritten signature and for this testimony to be communicated to the agency

Subpart C §11.300, Controls for Identification codes/passwords

Persons who use electronic signatures based upon use of identification codes in combination with passwords shall employ controls to ensure their security and integrity. Such controls shall include:

  • Maintaining the uniqueness of each combined identification code and password, such that no two individuals have the same combination of identification code and password.
  • Ensuring that identification code and password issuances are periodically checked, recalled, or revised (e.g., to cover such events as password aging).
  • Following loss management procedures to electronically deauthorize lost, stolen, missing, or otherwise potentially compromised tokens, cards, and other devices that bear or generate identification code or password information, and to issue temporary or permanent replacements using suitable, rigorous controls.
  • Use of transaction safeguards to prevent unauthorized use of passwords and/or identification codes, and to detect and report in an immediate and urgent manner any attempts at their unauthorized use to the system security unit, and, as appropriate, to organizational management.
  • Initial and periodic testing of devices, such as tokens or cards, that bear or generate identification code or password information to ensure that they function properly and have not been altered in an unauthorized manner.

Engineering requirements:

  • System shall employ user-level security, ensuring each user is required to maintain a unique username and password to access the system
  • System shall employ role-based permissions and limit access to only functionality required by the job role
  • System shall require each user have a unique username and password
  • System shall expire passwords after a set amount of time
  • System shall lockout users after a set amount of failed login attempts
  • System shall have documented password strength requirements
  • System shall obfuscate passwords when entered and displayed on User Interfaces
  • System shall store passwords in an encrypted manner, and never display, store, or transmit passwords in plain text

Procedural requirements:

  • Procedures shall exist for the administration of users into the system
  • Procedures shall exist for the routine use of computer systems

What Engineering or Procedural requirements do you think are critical for cloud-based computer systems? Comment below!

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Compliance in the Cloud: SaaS, PaaS, and IaaS

Hello good people of the world! Today’s post is the first in a series on compliant software in the cloud. Cloud software is characterized by running strictly in a web browser; no software is installed on a client’s local hard drive. Cloud software has significant advantages for users and vendors alike, so it is no surprise that it has become the standard for modern personal and business software applications.

It should also not be surprising that cloud software has made it’s way into compliant industries such as medical device, pharmaceutical, and biologic manufacturing, which is the focus of this blog. Vendors and customers alike want the advantages that cloud software bring.

And what are the main advantages? It’s all about distribution. With cloud software, vendors can push new features to users without any downtime or need for manual upgrading, installation, etc. Vendors can monitor software use, responding to bugs much more quickly, and can make improvements based on how users are actually using the software, without any additional overhead for the user.

It has been demonstrated that the data collected through the routine use of cloud software can be immensely valuable, and there’s the added bonus of what insights could be gained when Artificial Intelligence (AI)/Machine Learning (ML) is applied to these big data sets.

Current commercial offerings are often categories into three categories:

  • Software as a Service (SaaS)
  • Platform as a Service (PaaS)
  • Infrastructure as a Service (IaaS)

Going from top to bottom, IaaS is a service offering typically offering server hardware, server virtualization, data storage, and networking. PaaS would offer all that and additionally server operating system(s), middleware (such as load balancing software, malware protection, etc.), and runtime applications such as databases. SaaS would then offer all that and the specific software application to boot.

Examples:

  • IaaS: DigitalOcean, Rackspace, Amazon Web Services (AWS), Microsoft Azure, Google Cloud Platform (GCP)
  • PaaS: Heroku, Windows Azure, Google App Engine
  • SaaS: Dropbox, Salesforce, Zoom, Facebook

In medical device, pharmaceutical, and biologic manufacturing companies may use IaaS and/or PaaS to outsource some of their IT needs, and may use SaaS products for such functions as Enterprise Resource Planning (ERP), electronic Document Management (eDMS), Laboratory Information Management (LIMS), etc.

Stay tuned for future blog posts on the subject of compliant cloud computing concerns, including: existing solutions, the validation life-cycle, regulatory documentation expectations, data integrity concerns, 483s, and CSA (Computer Software Assurance).

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Oral Solid Dose – Unit Operations

Granulator at an OSD Plant in Vietnam

Hello good people of the world! Continuing the series on oral solid dosage forms, today we’re going to talk about unit operations typical in a oral solid dose manufacturing process.

Typical OSD processes may include some combination of weighing/dispensing, material transfer, blending, granulation, drying, milling/sieving, compression, encapsulation, and coating. Some considerations around each step may include:

  1. Weighing/Dispensing: includes sampling for quality purposes. Materials to be sampled typically include: APIs, excipients, primary and secondary packaging, cleaning agents. Sampling areas must be protected from contamination.
  2. Material Transfer: material flows should be documented and reviewed, with the intention of minimizing any contamination.
  3. Blending: materials are typically blended to ensure a uniform composition, prior to downstream process steps. Many methods exist, including: tumble blending, bin blending, and agitator mixers.
  4. Granulation: granulation is the process of combining particles into a granule. Many methods of granulation exist: wet massing/extrusion, high shear, spray, speronization, and hot melt extrusion, for example.
  5. Drying: the purpose of the drying step is to remove any excess moisture from the drug product. Drying methods include: tray , fluidized bed, and spray drying.
  6. Milling/Sieving: the purpose of this process step is to reduce granule size to conform to specification. Some methods include: impact/hammer mills, conical mills, and oscillating horizontal screens.
  7. Compression: compression is used to create tablets.
  8. Encapsulation: encapsulation is used to create capsules.
  9. Coating: coating is used to apply a coat to tablets

In the next post we’ll cover supporting equipment and quality systems. What process steps do you use in your OSD process? Comment below!

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Oral Solid Dose – Material Handling

Hello good people of the world! Continuing the series on oral solid dosage forms, today we’re going to talk about material handling. Oral solid dose manufacturing is typically a batch process, which means materials need to be transferred from step-to-step. Sometimes there is direct conveyance between steps, but often transfer is performed via Intermediate Bulk Container (IBC).

In terms of design, IBCs should be able to handle the worst-case (lowest) density material in the process. IBCs should be cleanable, especially if a single container will support many product manufacturing processes. IBCs should be designed in such a way that they drain easily. Charging/discharging must be considered.

IBCs may be transported on wheels, or by a pallet truck.

Discharging may be facilitated by applying vibrations to the IBC, either internally or externally.

For direct conveyance, gravity, pneumatic conveyance, and mechanical conveyors are options.

What considerations around material handling do you have in your OSD lines? Comment below!

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Oral Solid Dose – Equipment Cleaning

Hello good people of the world! Continuing the series on oral solid dosage forms, today we’re going to talk about equipment cleaning. OSD manufacturing equipment can be notoriously hard to clean, and manual cleaning procedures introduce high risk of contamination and carryover. It is recommended that any new or existing process equipment be cleaned with automated processes wherever possible.

The three automated cleaning processes typically used in industry are:

  • Clean-in-Place (CIP)
  • Wash-in-Place (WIP)
  • Clean-out-of-Place (COP)

CIP is done without moving the equipment, as the name implies, and uses a CIP skid to deliver cleaning and rinse solutions. CIP should not require any manual operations.

WIP is done in-place as well, but may include some manual operations, such as removing filters.

COP requires equipment to be moved to a wash station. Tanks and vessels are typically COP’d.

Some specific concerns related to cleaning OSD equipment include:

  • Dry Granulator/Roller Compactor cannot typically be CIP’d. Particularly the auger must be removed and COP’d.
  • Fluid Bed Dryers a large and complex, making cleaning difficult. Modern dryers will include CIP/WIP but typically still require manual cleaning of some parts.
  • Milling equipment typically requires the screen to be manually removed before any CIP/WIP.
  • Tablet presses can be difficult to clean, requiring many manual interventions prior to washing.
  • Capsule filling machines should be wettable to allow cleaning.
  • Tablet coaters should include WIP

Of course, cleaning processes, whether automated or not, need to be validated. Riboflavin tests may be performed to verify wash coverage, and swabbing can verify lack of residual API and cleaning solutions.

What challenges have you run into in cleaning your OSD manufacturing equipment? Comment below!

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Oral Solid Dose – Equipment

5be972ca47be7

Hello good people of the world! Today’s post is the third in the series covering the commissioning, qualification, and validation of facilities, systems, and equipment involved in the manufacture of oral solid dose (OSD) products. This post covers the equipment used to manufacture these products.

Considerations include: materials of construction, sampling, and cleanability.

  1. Materials of Construction: it is critical that equipment materials do not react with or otherwise adulterate the product being manufactured. Materials of construction may be metals (e.g. 316L stainless steel), plastics, or elastomers. Other considerations include design documentation, surface finish including at welds, and any certification required.
  2. Sampling: equipment must be designed so that sampling is facilitated where required. Sampling is typically a mitigation for product quality failure modes such as content uniformity in granulation, over/under drying in drying, failed particle size distribution in milling, leakage in encapsulation, and over spray in coating, among others.
  3. Cleanability: automated clean-in-place (CIP) cleaning procedures are preferred where practical. Manual cleaning and sterilization may also be considerations.

What do you think about in terms of your OSD manufacturing equipment?

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Oral Solid Dose – Critical Properties

Hello good people of the world! Today’s post is the first in a series covering considerations around the commissioning, qualification, and validation of facilities, systems, and equipment involved in the manufacture of oral solid dose (OSD) products. OSD is a wide-spread method of pharmaceutical delivery, including well known medicines such as aspirin, Viagra, and many antibiotics. Solid doses can take the form of powders, tablets, capsules, pills, lozenges, granules and more.

Here we’re going to cover the physical and chemical properties that should be considered in equipment design.

First, environmental factors:

  1. Temperature and Humidity: temperature and humidity should be controlled even if the product is not sensitive, as most processes are susceptible to flow issues in the extreme temperature and/or humidity ranges.
  2. Light: some OSD products are light (especially UV light) sensitive and must be protected from sunlight and even indoor light in some cases.
  3. Oxygen: some products may also be sensitive to oxygen exposure.

Second, process factors:

  1. Particle size and size distribution: powders inevitably have some variation in particle size that must be understood and controlled
  2. Particle shape: similarly to size, particles will have variation in shape
  3. Surface properties: are the particles smooth or rough? Do they stick together? Do they readily absorb moisture? Surface properties must be understood
  4. Particle strength: particles will break down under enough force. Particle strength must be understood and undue stress avoided in manufacturing processes.
  5. Density, porosity, and packing: how does a particle pack? Things like minimum bulk density, poured bulk density, and tapped bulk density should be understood.
  6. Cohesion in powders: related to surface properties, how to particles stick together? Magnetic, electrostatic, and intermolecular forces may be in play and should be understood.

What factors do you consider in your OSD manufacturing process?

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Validation Program Tenets

Hello good people of the world! What are the overarching tenets that you go to when making decisions related to your validation program? The regulations and guidance from industry only go so far and you will be regularly tasked with situations unique to your program. How do you know what is the right way to go in the grey areas? I like to keep these tenets in mind:

  1. The manufacturing process should be the most complex process on the site. Reduce complexity everywhere else. Reduce the number of deliverables. Reduce the number of process steps.
  2. Requirements feed specifications feed test protocols. Remember that you should always be able to trace a test case to a requirement through the specifications.
  3. Compliance is not binary, you are accepting degrees of regulatory risk. Make sure you understand the risk and that you accept it.
  4. Good Manufacturing Practices are not just from the CFRs. World-wide best practices need to be considered and applied where applicable.
  5. It’s all about documentation. If it’s not documented it didn’t happen. Create a logical narrative, and you’re already mostly there.
  6. Our primary purpose is to create documentation for agencies. Take any kind of writing class, and one of the first things you’ll learn is: know who your audience is and write for them. While it’s great the validation documentation can be used for commissioning, process improvement, etc. that must not come at the cost of it’s primary purpose.

What are some of your go-to tenets?  Comment below.

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PLC/HMI IOQ – What to Test?

PLC

Hello good people of the world! Today’s post is on initial control system Installation and Operational Qualification (IOQ) of a simple system consisting of an Human/Machine Interface (HMI), Programmable Logic Controller (PLC), and any number of end devices (valves, pumps, sensors, etc.). The question is what should be tested?

Obviously there’s a ton of guidance out there (see e.g.: GAMP) that will have a lot more detail than this post. The purpose here is to list at a high level the tests that could be expected. So let’s get started!

Installation Qualification
IQ can be its own protocol or combined with OQ in an IOQ for cases without a ton of complexity. IQ is supposed to verify the installation of hardware, software, and any peripherals. You also want to check what documentation is available/applicable here. IQ tests may include:

  • Documentation Verification (e.g. SOPs, EREC/ESIG assessment, operating/maintenance manuals, panel and electrical drawings, etc.)
  • Hardware Verification: verify the make and model of major components at a minimum
  • Software Verification: verify/record software versions. You’ve got to know what you’ll be OQ’ing!
  • Configuration Verification: verify any hardware and/or software configuration. This could be two tests, one for hardware, one for software.
  • Loop Check Verification: verify loop checks are performed.
  • Alarm Configuration Verification: ideally alarms a setup in such a way that you don’t have to functionality test them all!
  • Any other critical installation items

Operational Qualification
OQ is the meat of your control qualification. Here you want to test critical functions, that hopefully you have identified earlier (see here for one approach). OQ may test:

  • Interlock Verification including e-stops. A lot of interlocks are safety/business related, but they’re often included in OQ due to how critical they are.
  • Functional Alarm Verification – be sure to include data loss/communication alarms
  • HMI Navigation and Layout Verification
  • Restart/Recovery Verification
  • Sequence of Operations Verification

What kinds of testing are you sure to cover in your control system IOQ protocols? Comment below.

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