The European Commission released a draft revision to Annex 1 “ Manufacture of Sterile Medicinal Products” on December 20, 2017. The revisions have several major changes that will impact your sterile products and drug substance manufacturing. This revision introduces Quality Risk Management for use with new technologies and processes and includes updates to the recommendations on clean rooms, sealing technologies and single-use systems. It also includes a new section on “Utilities” covering water, sterilization, filtration and cooling systems used for production of sterile products. The draft is available for public comment until March 20, 2018.
Happy New Year! MWA is off and running to a busy 2018. Our feature article for January 2018 is a summary of FDA 483 observations from 2017. This information can help you focus your resources to ensure your company is in compliance with the current FDA regulations and concerns as well as enhance your training programs.
Here is the complete spreadsheet of observations from the FDA website (link will download as an Excel file) from Fiscal Year 10/1/2016 – 9/30/2017. It includes summaries for Biologics, Bioresearch Monitoring, Devices, Drugs, Foods, Human Tissue, Parts 1240 and 1250, Radiological Health and Veterinary Medicine.
MWA’s regulatory compliance consulting experts can help you formulate the correct response to FDA 483 observations. Our staff includes highly experienced subject matter experts who can help your firm craft a clear and accurate response to technical inquiries for GXP reviewers as well as warning letters and technical questions to Regulatory Agency centers. Responding to a Regulatory Agency is only the first step. MWA will also provide you with a clear remediation and corrective action plan and help you implement the specific actions quickly and efficiently.
For Drugs, the most common violations were related to Production Record Review; Organization and Personnel: The QC Unit and Personnel Qualifications; Laboratory Controls; Production and Process Controls: Written Procedures Deviations and Control of Microbial Contamination.
For Devices, the most common violations were Corrective and Preventive Action; Records: Complaint Files and Device History Records; Production and Process Controls, Process Validation; Design Controls, Design Validation; Quality System Requirements, Quality Audits; and Purchasing Controls.
Ensuring data integrity is a crucial task for drug manufacturers wishing to stay out of trouble with the FDA, a top enforcement official at the agency told an industry conference.
“Everything else that we do is based on the integrity of the data,” Douglas Stearn, the director of the Office of Enforcement and Import Operations in the Office of Regulatory Affairs, said at the 12th annual FDA Inspections Summit, sponsored by FDAnews. “When you’ve got this problem, you’ve got a very big problem.”
The FDA views data integrity as a good manufacturing practice issue, and the agency can determine that a product is adulterated if it uncovers evidence of falsification, manipulation or concealment of data about test results, batch processing or other operations, Stearn said.
Sometimes companies land in hot water over issues that can seem “shockingly small,” such as falsification of work records to generate unearned overtime payments, which can raise questions about overall control of the information system. Managers may be unaware of these problematical practices, so accountability is key, he said.
“Innocent people can be put in a bad place,” Stearn said. “Your system should be able to tell who’s on it, and doing what.”
In the years after the Hatch-Waxman act was passed in 1984, the generic drug industry was hit by scandals that still cast a shadow over the FDA’s policing of data integrity, Stearn said. Companies manipulated data to move their abbreviated new drug applications to the front of the line, and in one case, an FDA reviewer was prosecuted for taking payoffs, Stearn said.
Data integrity enforcement is changing as more records are computerized and more foreign companies join the drug supply chain, he said. It can be difficult for the agency to prosecute violators abroad because of the absence of subpoena power and different practices regarding court summonses and evidence, Stearn said. Another check on American enforcement clout in India and China, the largest overseas drug producers, is the lack of extradition treaties between those two countries, respectively, and the United States, he said.
Stearn pointed drug manufacturers to two reference sources for data integrity guidelines:
• FDA regulations, which include requirements such as “backup data are exact and complete,” data is “secure from alteration, inadvertent erasures, or loss”, certain activities are “documented at the time of performance” and that a company maintain “complete records of all tests”.
The USP General Chapters—Packaging and Distribution Expert Committee proposes two new general chapters to address the qualification of polymeric components used in the manufacture of both pharmaceutical and biopharmaceutical active pharmaceutical ingredients (APIs) and drug products (DPs):
Chapter 665 Polymeric Components and Systems Used in the Manufacturing of Pharmaceutical and Biopharmaceutical Drug Products;
Chapter 1665 Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products.
The drafts of these two chapters have been published for public comment in Pharmacopeial Forum (PF) 43(3) [May–Jun. 2017]. Deadline for comments is July 31, 2017.
Chapter 665 was initially published as Plastic Components and Systems Used in Pharmaceutical Manufacturing 661.3 in PF 42(3) [May–June 2016]. The current proposals take into account comments received on the 661.3 proposal and from the USP Biocompatibility and Material Characterization Workshop held June 20–21, 2016. The chapter number 1665 was previously assigned to a proposed new general chapter Toxicological Safety Assessment of Extractables and Leachables (announced in the stimuli article “USP Plastic Packaging General Chapters: An Overview” in PF 39(6)). However, chapter number 1665 is now assigned to the proposed new general chapter Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products.
Chapter 665 is structured as follows:
3. ASSESSMENT PROCESS
3.1 Initial Assessment:
Examines whether a polymeric material, component, or system is fit for its intended use (with respect to patient safety) without further characterization.
The first and second steps consider whether there is contact between a component and a process stream and whether the process stream that contacts the polymeric material, component, or system is a liquid.
The third step considers whether the material, component, or system is used to manufacture an approved and marketed API, DS, or DP. If a material, component, or system has been established to be acceptable, further characterization of the material, component or system is not required, providing this is justified.
The last step considers whether the component or system under assessment is equivalent to a component or system that has already been established to be acceptable (a comparator). For example, a component that is used to manufacture an approved drug product could be a comparator for a second, but similar, component used to manufacture a different, but similar, drug product. In order to link a component or system to a comparator, reference is made to Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products(chapter 1665).
When a comparator has been established for the component under assessment, then further characterization of the material, component, or system is not required as long as a justification is provided. When a comparator cannot be established, proceed to 3.2 Risk Assessmentto establish the appropriate and necessary level of material and component testing.
3.2 Risk Assessment:
The testing of materials and components is driven by the risk that the material or component could be unsuited for its intended use. The greater the risk that the material or component could be unsuited for use, the greater the degree of required testing. Risk assessment is accomplished via application of a Risk Assessment Matrix detailed inPlastic Components and Systems Used to Manufacture Pharmaceutical Drug Products (chapter 1665).
The outcome of this assessment establishes three levels of risk: low (level A), moderate (level B), and high (level C). These levels are linked to the test requirements defined in section 4.2.1 and 4.2.2.
If a component has been tested according to this chapter and meets the specifications contained in this chapter, the component’s materials of construction are deemed to be compliant with this chapter without having been tested according to (chapter 661.1).
If the component meets the plastic class VI requirements according to USP general chapter 88, it is not necessary to test the component according to chapter 87.
POLYMERIC MATERIALS OF CONSTRUCTION
4.1 Plastic Materials Not Addressed in chapter 661.1
4.2 Cured Polymeric Materials
4.2.1 Test Methods
4.2.2 Specifications5. POLYMERIC COMPONENTS AND SYSTEMS
5.1 Test Methods
(Manufacturing components or systems that do not meet the requirements of the relevant biological reactivity tests (chapters 87 and 88, as appropriate) are not suitable as manufacturing components or systems for pharmaceutical and/or biopharmaceutical use);
2. SCOPE3. GENERAL PRINCIPLES
3.2 Material Characterization and Selection
3.3 Component Characterization and SelectionCHARACTERIZATION PROCESS
4.1 Initial Assessment
4.2 Risk Assessment
4.2.1 Risk evaluation matrix
4.2.2 Application of the risk evaluation matrix
4.2.3 Using the risk evaluation matrix
4.2.4 Linking risk to characterization methodologies4.3 Establishing the Level of Characterization
4.3.1 Baseline assessment
4.3.2 Expanded baseline assessment
4.3.3 Full testing (extractables profiling)4.4 Standard Extraction Protocol
4.4.1 Extraction solvents
4.4.2 Extraction temperature
4.4.3 Extraction duration
4.4.4 Accomplishing the extraction
4.4.5 Non-standard extractions
4.4.6 Accounting for conditioning and related steps employed in manufacturing4.5 Testing the Extracts and Generating the Extractables Profile
4.6 Evaluation of the Extractables Profile Established by Implementing the Standard Extraction Protocol5. SAFETY QUALIFICATION
5.2 Chemical Safety Qualification
5.3 Additional Safety QualificationGLOSSARY
At times of outsourcing and globalisation, the significance of Certificates of Analysis (CoA) is growing. Ultimately, the user of such certificates has to rely on their accuracy and completeness.
There are CoAs for excipients, APIs, packaging materials and finished products. A closer look at the guidelines shows that there are a few regulatory requirements which are often unknown. Requirements can be found in the following sets of rules:
EU GMP Guide Part I (Chapter 4 and Chapter 6)
EU GMP Guide Part II – Section 11.4
EMA Guideline on batch certification (Internationally harmonised Requirements for Batch Certification)
WHO Annex 10 – Model Certificate of Analysis
USP General Chapter <1080> Bulk Pharmaceutical Excipients – CoA
IPEC CoA Guide for Pharmaceutical Excipients
According to the EU GMP Guide Part I, certificates of analysis provide an overview of test results obtained from a product or a material. This also includes the assessment of compliance with the specification determined.
Section 11.4 of the EU GMP Guide Part II on certificates of analysis requires an authentic certificate of analysis for each batch of an intermediate or API. Among other things, this certificate should contain the following information:
Name of the intermediate or API
List of the tests performed including acceptance limits
Dated signature by authorised personnel
Name of the company
or Name of the laboratory
You can find specific requirements regarding CoAs in these GMP guidelines. This is a difference to other quality guidelines like e.g. ISO 9001, where you don´t have this concretisation.
Is adhering to ICH Good Clinical Practice guidelines enough to ensure compliance?
The European Medicines Agency’s latest guideline says clinical trial master files should also include quality reports and checklists, product certifications and trial-specific computer system guides. These essential documents are not listed as required in ICH Good Clinical Practice guidelines. This guideline includes the following:
• Documentation that would help evaluate the trial’s conduct should be included in the file, whether they were explicitly listed in guidelines or not.
• Both paper and electronic TMF information should be verifiable with an audit trail and should protect subject confidentiality.
• TMF organization should segregate documents held by the sponsor and those held by the investigator, while avoiding duplication (i.e., separating product-development level documents such as training records, SOPs or product brochures, as well as relevant GMP information).
• Clinical master files must be archived for at least 25 years following the end of the clinical trial. For all trials that support a marketing authorization, essential documents must be retained for at least 15 years, or at least 2 years after the last approval. Subject medical files should be retained in accordance with national regulations.
News from the Parenteral Drug Association (PDA): The The recently revised United States Pharmacopoeia (USP) chapter <1116> Microbiological Control and Monitoring of Aseptic Processing Environments includes a thorough description, definitions and guidance on microbiological control and monitoring in aseptic processing environments.
Chapter <1116> is arguably one of the most comprehensive informational chapters from the USP, and it is particularly challenging due to its proposal regarding measurement of microbial contamination based on Contamination Recovery Rates (CRR) rather than the conventional enumeration of colony forming units (cfu). Instead of using the microbial limits currently endorsed by aseptic guidances—which are based on cfu—<1116> proposes CRR values expressed in maximum allowed percentage of contaminated samples. The proposal is generating a broad range of discussions among pharmaceutical professionals regarding potential implications of these changes.
Do your standards require compliance with multiple compendia? You may be able to simplify your standards testing.
The latest addition of the MAPP (Manual of Policies and Procedures) 5310.7 – Acceptability of Standards from Alternative Compendia (BP/EP/JP) published in January 2017 states that it is reasonable to accept an applicant’s proposal to use a quality standard from the BP, EP, or JP as part of the specifications for an excipient, drug substance, or drug product in the drug application, if the standard in the BP, EP, or JP is equivalent to or better than the corresponding standard in the USP/NF.
This is useful information for those responsible for marketing authorization or incoming goods control in the pharmaceutical industry.
In the finalized guidance on GMP requirements for combination product manufacturers, the FDA clarified how to comply with certain device requirements with compliance examples for prefilled syringes, drug-coated mesh and drug-eluting stents. This final version reiterates that combination product manufacturers have two options for compliance: satisfy all drug and device GMPs, or implement a streamlined quality system that focuses primarily on one but incorporates elements of the other GMP systems. This guidance details which GMPs are applicable to a product, general methods for how to implement them, key definitions, and how to make post-market changes to a product’s quality system.
A recent case from Denmark demonstrated that senior management really is responsible for GMP compliance. The Danish Medicines Agency (DKMA) has now taken an action that reinforces senior management responsibility in a very significant way: they demanded the replacement of the CEO!
It’s important that senior management understand their critical role in implementing a compliant Pharmaceutical Quality System (PQS) and in creating a good quality culture.