Pharmaceutical manufacturing regulations and standards

Ampoule filling and sealing machine

Today, the pharmaceutical industry is dealing with the need to expedite the process of drug development and the demands of global competition. The industry also faces expectations set by the Food and Drug Administration (FDA) to use process analytical technology and the principles of quality in process and analytical development.

 

Accordingly, pharmaceutical manufacturing needs to meet high standards to ensure purity and quality for its final products and the strength of the product's active ingredients. The standards are set to ensure consumers receive safe, effective products. Utilizing an industrial software platform like zenon can help your company control processes, automate a variety of functions, track data and- most importantly- adhere to pharmaceutical manufacturing standards and regulations. 

 

The importance of good manufacturing practices

Guidelines for Good Manufacturing Practices (GMPs) help manufacturers improve their production of goods, ensuring that consistent procedures are executed within safe environments. GMPs also prevent recalls, contamination and loss of profit.

 

In the United States, there are two sets of Good Manufacturing Practice standards defined by the FDA. One set of standards refers to the food industry and the other refers to the pharmaceutical industry. In Europe, the European Union provides GMP guidance. Similar validations for current Good Manufacturing Practices are used in other countries like Canada, Australia and Japan. In the UK, the Medicines Act covers most of the GMP aspects.

 

In 1997, the FDA issued regulations that provide companies criteria for achieving FDA acceptance. All of these regulations apply to every FDA program area, permit the widest use of electronic technology and are compatible with the FDA's responsibility to protect public health. To ensure your pharmaceutical products are effective, safe and high-quality, adhere to the current Good Manufacturing Practices below.

 

What is cGMP for drug manufacturers?

The pharmaceutical industry manufactures a variety of essential products, which has resulted in highly profitable businesses in this sector. Pharmaceutical manufacturers also face many unique challenges, as the industry is one of the most heavily regulated. Pharmaceutical companies must constantly monitor compliance with international and local standards and regulations.

 

Good Manufacturing Practices refer to the production standards that regulators, consumers and retailers have embraced in the drug industry. They offer basic assurance that a pharmaceutical product was produced under conditions that met industry standards. Some of the areas that GMPs address include:

 

  • Employee practices
  • Reports and records
  • Conditions of sanitation
  • Sourcing of raw ingredients
  • Facility and building conditions
  • Equipment maintenance and design
  • Maintaining strong controls of production

 

The current Good Manufacturing Practices (cGMP) in the drug industry address the production of pharmaceutical drugs that will be sold in the United States. In the U.S., cGMPs are regulated by the FDA. To meet pharmaceutical manufacturing regulations and standards, follow Good Manufacturing Practices guidelines.

 

The difference between GMP and cGMP

GMP refers to Good Manufacturing Practice and cGMP refers to current Good Manufacturing Practice. cGMP is an acronym that originated in the U.S., where the U.S. Food and Drug Administration aimed to convince drug manufacturers of the need to continuously improve the approach to product quality.

 

The FDA cautions against using a "set it and forget it" approach for GMP guideline compliance. Instead, manufacturers should ensure product quality is a core driver in their organizations.

Failure to comply with the standards and regulations in the pharmaceutical industry can lead to massive problems!

Consequences of failing to meet standards

Adhering to the current Good Manufacturing Practices and meeting standards ensures manufacturing operations are adequately controlled and the strength, identity, purity and quality of drug products are assured.

 

Failure to comply with the standards and regulations in the pharmaceutical industry can lead to:

 

  • Costly fines
  • Unsafe products
  • Delays in product approval
  • Unlabeled products
  • Criminal charges

 

However, when you achieve GMP compliance, you can enjoy the following benefits:

 

  • Access to buyers who mandate GMP compliance from suppliers
  • Leverage over competitors without GMP compliance
  • Compliance with supplier verification requirements, which can mean less back-and-forth between other companies and your team

 

This need to comply with the industry standards and regulations means each step of the pharmaceutical manufacturing process should be thoroughly documented and traceable. For instance, in the supply chain, pharmaceutical manufacturers mandate end-to-end transparency.

 

As there is a high level of risk in the pharmaceutical industry, many manufacturers are hesitant to shift away from paper documentation and implement the digitalization of the pharmaceutical manufacturing plant. As patents for drugs expire, though, efficiency in production becomes increasingly crucial. 

 

Regulations in the pharmaceutical industry

By carefully monitoring whether drug manufacturers are compliant with the Current Good Manufacturing Practice regulations, the FDA ensures the quality of pharmaceutical products. For drugs, the CGMP regulations include minimum requirements for the controls, facilities and methods used in processing, manufacturing and packing a drug product.

 

Regulations ensure a drug product is safe for use and includes the strength and ingredients it claims to have. For a generic or new drug to be approved, the manufacturer's compliance with cGMPs will be reviewed. The FDA investigators and assessors will determine whether a firm has the necessary ability, equipment and facilities to manufacture a drug it intends to market.

 

The FDA's portion of the Code of Federal Regulations is in Title 21, which interprets the Federal Food, Drug and Cosmetic Act. The regulations listed in this section allow for an understanding of the regulatory process by describing the requirements that should be followed by the FDA, applicants and drug manufacturers. The following are the main regulations affecting pharmaceutical manufacturers:

 

21 CFR Part 210 — cGMP in manufacturing, processing, packing or holding of drugs

The regulations in 21 CFR Part 210 refer to current Good Manufacturing Practice in the processing, manufacturing, holding or packing of drugs. This section includes the controls or facilities to be used for, and the methods to be used in, the processing, manufacturing, holding or packing of a drug to assure it meets the requirements of safety and meets the purity and quality characteristics that it purports to possess. Failing to comply with this regulation will render the drug to be adulterated and the person responsible for the compliance failure will be subject to regulatory action.

For data integrity, data should meet the ALCOA principle: Attributable, Legible, Contemporaneous, Original and Accurate!

21 CFR Part 211 — cGMP for finished pharmaceuticals

The regulations in 21 CFR Part 211 refer to current Good Manufacturing Practices in regards to finished pharmaceuticals and the process of preparing drug products for administration to animals or humans. Current Good Manufacturing Practice includes requirements about:

 

  • Equipment
  • Laboratory controls
  • Reports and records
  • Personnel and organization
  • Labeling and packaging control
  • Process and production controls

 

To guarantee data integrity, data should meet the ALCOA principle — Attributable, Legible, Contemporaneous, Original and Accurate. The Attributable principle states that the process and person are linked to the record intrinsically. The following subparts are related to the Attributable principle:

 

  • 211.101(d):Under the section on the charge-in of components, every component should be added to the batch by a single person and verified by another or verified by only one person if automated equipment adds the components.
  • 211.122:This section refers to materials examination and usage criteria. This section includes requirements on written procedures, labelling or packaging materials, visual inspections and printing devices on manufacturing lines.
  • 211.186:This section refers to master production and control records and is intended to assure uniformity across every batch. These records include a product's name and strength, name and measure or weight of every active ingredient, list of components and description of the drug product closures, packaging materials and containers.
  • 211.188(b)(11): This subpart refers to identifying the people who are performing and checking or supervising every significant step in the operation. This also applies if one of the operation's significant steps is performed by automated equipment.
  • 211.180(e): This part requires written records that should be maintained so the data can be used to evaluate each drug product's quality standards. This evaluation determines whether there is a need for changes in the manufacturing, specifications or control procedures of the drug product.

 

The Contemporaneous principle states that electronic data should be recorded and time-stamped immediately as the event occurs. The following subparts are related to the Contemporaneously recorded principle:

 

  • 211.100(b): Under the section on written procedures, this part refers to process control and written production procedures. These should be documented while being performed, and any deviations from written procedures should be recorded and justified.
  • 211.160(a)Under the section on general requirements, the establishment of standards, specifications, test procedures and sampling plans, including any changes, should be drafted by the proper organizational unit and approved and reviewed by the quality control unit. During the time of performance, the requirements in this part should be followed and documented.

 

The Original principle states that the electronic data should be a true representation of the process. The following subparts are related to the Original principle:

 

  • 211.180: This section refers to the general requirements of records and reports related to cGMP for finished pharmaceuticals. Requirements included in this section refer to how long records should be retained and whether records should be retained as original or true copies.
  • 211.194(a)Under this section, it is specified that laboratory records should include data from the tests needed to assure compliance with established standards and specifications, including assays and examinations.

 

The Accurate principle states that electronic data should be accurate in time, measurement and context of the process, person and equipment. The following subparts are related to the Accurate principle:

 

  • 211.22(a):Under the section on responsibilities of the quality control unit, you should have a quality control unit that has the responsibility and authority to reject or approve components, closures, labelling, drug product containers and in-process materials. This unit also can review production records to ensure errors have not occurred or that errors are fully investigated.
  • 211.68: This part refers to automatic, mechanical and electronic equipment. These systems should satisfactorily perform a function and can be used in a drug product's processing, manufacturing, packing and holding. Equipment should be regularly inspected, checked or calibrated, and written records of these inspections and calibrations should be maintained.
  • 211.188: This section details batch production and control records. These records should be prepared for every batch of produced drug product and should include information about the control and production of each batch. These records should include several different items, such as dates, documentation of each significant step and identification of major lines and equipment used.

 

21 CFR Part 212 — cGMP for positron emission tomography drugs

The regulations in 21 CFR Part 212 refer to current Good Manufacturing Practice in regard to positron emission tomography (PET) drugs. These current Good Manufacturing Practices are the minimum requirements for the controls and facilities used for, and the methods used in, the production, distribution, quality assurance or holding of these drugs as intended for human use.

 

The intention of current Good Manufacturing Practice is to ensure that every PET drug meets the standards and requirements of safety, strength and identity, along with meeting the purity and quality characteristics the drug should have. The following subparts are related to the Attributable principle:

 

  • 212.50(c)(10): This section refers to control and batch production records. A batch production and control record should be created when a batch of a PET drug is produced. The record should include the PET drug's name and strength, identification number, every major production step, dates and times of production steps, labelling, identification codes and weights of components and testing results.
  • 212.110(b): This part details the quality of the records you should maintain for the production of PET drugs. All records need to be legible, readily available for review and stored to prevent loss or deterioration.

 

Subpart 212.60(g) is related to the Accurate principle. This part refers to the test records under the section on requirements that apply to laboratories where products, components and materials are tested. When a laboratory performs tests relevant to a PET drug's production, records must be completed of all the tests performed to make sure the laboratory is in compliance with established standards and specifications.

 

21 CFR Part 600 — biological products

Finally, the regulations in 21 CFR Part 600 refer to biological products in general. These regulations of current Good Manufacturing Practices pertain to the drugs that are biological products for human use. The subparts of 21 CFR Part 600 refer to:

 

  • General provisions
  • Establishment inspection
  • Reporting of adverse experiences 
  • Establishment standards

 

For example, establishment standards include requirements for personnel, equipment, physical establishment, records, temperatures during shipment, retention samples and reports on biological product deviations.

 

Personnel should have capabilities that are commensurate with assigned functions, the necessary experience and training relating to individual products, and an understanding of the manufacturing operations they perform. Personnel should include all the professionally trained persons who are necessary to ensure that all manufacturing processes are competently performed.

With zenon, FDA 21 CFR Part 11-compliant projects and EU Annex 11 projects are created out-of-the-box!

European norm issued by EMA

In the European Union, the rules that govern medicinal products include guidance for interpreting the principles of Good Manufacturing Practices for human and veterinary medicinal products:

 

  • EU GMP Part I: Part I addresses the basic requirements for medicinal products. This part includes chapters on personnel, pharmaceutical quality system, documentation, quality control, production, outsourced activities, self-inspection, premise and equipment, and complaints and product recall.
    According to data Integrity ALCOA principle, we should refer the following chapters:
    • Attribuitable: Ch. 4.20 c&f, 4.21 c&i, 4.29 e
      Legible: 4.1, 4.2, 4.7, 4.8, 4.9, 4.10
      Contemporaneous: 4.8
      Original: 4.9, 4.27, Paragraph Record
      Accurate: 4.1, 6.17
  • EU GMP Part II: Part II addresses the basic requirements for active substances used as starting materials. These requirements place obligations on manufacturing authorization holders to only use active substances that have been manufactured according to GMP for starting materials.
    According to data Integrity ALCOA principle, we should refer the following chapters:
    • Attributable: Ch. 6.14, 6.18, 6.52
      Legible: 5.43, 6.11, 6.14, 6.15, 6.50
      Contemporaneous: 6.14
      Original: 6.14, 6.15, 6.16
      Accurate: 5.40, 5.45, 6.6
  • EU GMP Annex 11: Annex 11 refers to computerized systems used as part of GMP-regulated activities. There are general requirements for personnel, risk management, suppliers and service providers.
    According to data Integrity ALCOA principle, we should refer the following chapters:
    • Attributable: Ch. 2, 12.4, 15
      Legible: 7.1, 9, 10, 17
      Contemporaneous: 12.4, 14
      Original: 8.2, 9
      Accurate: Ph. “Principles”, Ch. 5, 6, 10, 11

How zenon can help manufacturers meet regulations

At COPA-DATA, our pharmaceutical manufacturing software, zenon, was developed to help companies optimize processes with innovative technology and overcome industry challenges. zenon makes it simple for you to execute and control your production line. GMP projects and FDA 21 CFR Part 11-compliant projects and EU Annex 11 projects are created out-of-the-box. For pharma operations, this software is the ideal human machine interface (HMI) due to its capabilities and templates. zenon's standardized software platform makes the following tasks easier:

 

Validation efficiency

When considering the extent of the validation of your computerized systems, take into account what impact these systems have on your ability to adhere to the predicate rule requirements. Additionally, consider the effect those systems may have on the reliability, accuracy, authenticity, availability and integrity of required signatures and records.

 

Even if there isn't a predicate rule requirement for validating a system, you may still want to validate it. We recommend you base your approach on a documented and justified risk assessment and a determination of the system's potential to affect record integrity and product safety and quality.

 

In pharmaceutical production, zenon allows for simple and easy processes, from small quantities to mass production. This platform ensures transparency, and in the validated environment, supports continual improvement processes. With zenon, project engineering becomes flexible and reliable in the pharmaceutical industry. Your company can also couple this with greater potential for innovation and reduced validation work.

 

Compliance with regulations

With zenon, complying with regulations is made easy. A pharmaceutical manufacturer's digitization system should comply with all the applicable regulations at the local and international level. At COPA-DATA, we can help minimize the effort needed to achieve compliance. zenon meets the FDA 21 CFR Part 11 GMP guidelines. The Software Platform allows users to record data directly at the machine panel or digitally using mobile devices, eliminating the need for paper checklists.

 

Recipes Management and Batch Control

In zenon, ISA 88 Process Automation and recipe management are characterized by flexibility and user-friendliness. Documentation and reporting are thoroughly automated in our standardized software platform. As a result, production and quality assurance can be combined seamlessly, as quality analyses and reports are available at the simple touch of a button.

 

Simplify engineering

At COPA-DATA, our line execution system includes features like alarming, central data management and connectivity with third-party devices and apps. zenon can also inform quality assurance and detect deviations from Good Manufacturing Practices.

 

Because of the openness of zenon, the monitoring of centralized technical services and building management can be implemented in a holistic system. With this, you can improve your entire system's productivity. The out-of-the-box usability ensures you are able to use zenon right away, and enjoy the following benefits:

 

  • Design flexibility
  • User satisfaction
  • Easy application of operating concepts

 

No programming is required. All you need to do is set parameters, and you'll be able to complete complex projects with little fuss.

 

Production expansion

With zenon, you can also enjoy production expansion. With this increased productivity, lower production costs are likely to follow, which can further boost your bottom line. When you choose zenon, you can establish a runtime system that is fully functional without adding extra servers.

 

Reducing costs for production and manufacturing means identifying inefficiencies, assessing your processes and making targeted changes. While giving you easy access to the data needed to make changes, zenon also reduces the financial risk that comes with non-compliance.

 

Contact COPA-DATA with questions

With zenon's standardized software platform, you can add features and modules as you need. The platform encompasses the following features:

 

  • HMI
  • SCADA
  • Alarming
  • Soft PLCs
  • Historian
  • Reporting
  • Messaging

 

You can use our software to monitor, automate, analyze and control your operational processes. As a pharmaceutical manufacturer, zenon can make your life easier and leave a substantial impact on your business.

 

COPA-DATA has over 30 years of experience in the industry, and we are continuously improving the software to make sure it maintains all the necessary logic and algorithms. Contact us today with questions about regulations for pharmaceutical manufacturing or the products and services we offer.

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